Compounds having affinity at 5ht2C receptor and use thereof in therapy

ABSTRACT

Compounds of formula (I) or a pharmaceutically acceptable salt thereof are disclosed:  
                 
 
     wherein R 1  is hydrogen, hydroxy, fluoro, chloro, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, C 1-6 alkoxy or haloC 1-6 alkoxy; m is 0 when  
                 
 
is a double bond and m is 1 when  
                 
 
is a single bond; R 2  is hydrogen, halogen, cyano, nitro, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkylthio, amino, mono- or di-C 1-6 alkylamino or an N-linked 4 to 7 membered heterocyclic group; X is —(CH 2 —CH 2 )—, —(CH═CH)—, —(CH 2 ) 3 —, —C(CH 3 ) 2 —, —(CH═CH—CH 2 )—, —(CH 2 —CH═CH)— or a group —(CHR 5 )— wherein R 5  is hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy or C 1-6 alkylthio; R 3  is halogen, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, C 1-6 alkoxy, C 1-6 alkylthio, hydroxy, amino, mono- or di-C 1-6 alkylamino, an N-linked 4 to 7 membered heterocyclic group, nitro, haloC 1-6 alkyl, haloC 1-6 alkoxy, aryl, arylC 1-6 alkyl, arylC 1-6 alkyloxy, arylC 1-6 alkylthio or COOR 6 , CONR 7 R 8  or COR 9  wherein R 6 , R 7 , R 8  and R 9  are independently hydrogen or C 1-6 alkyl; p is 0, 1 or 2 or 3; R 4  is hydrogen, halogen, hydroxy, cyano, nitro, C 1-6 alkyl, C 1-6 alkanoyl, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, haloC 1-6 alkyl, C 1-6 alkoxy, haloC 1-6 alkoxy, C 1-6 alkylthio, amino, mono- or di-C 1-6 alkylamino or an N-linked 4 to 7 membered heterocyclic group; Y is oxygen, sulfur, —CH 2 — or NR 10  wherein R 10  is hydrogen or C 1-6 alkyl; D is a single bond, —CH 2 —, —(CH 2 ) 2 — or —CH═CH—; and Z is an optionally substituted C-linked 4 to 7 membered heterocyclic group containing at least one nitrogen, an optionally substituted N-linked 4 to 7 membered heterocyclic group, or Z is —NR 11 R 12  where R 11  and R 12  are independently hydrogen or C 1-6 alkyl. Methods of preparation and uses thereof in therapy, particularly for CNS disorders such as depression and anxiety, are also disclosed.

This invention relates to novel compounds having pharmacologicalactivity, processes for their preparation, to compositions containingthem and to their use in the treatment of CNS and other disorders.

WO 96/23783, WO 97/46699 and WO 97/48700 all disclose a series ofindoline derivatives which are 5-HT_(2C) receptor antagonists and whichare claimed to be useful in the treatment of various CNS disorders.

A novel class of compounds possessing 5-HT_(2C) receptor activity hasbeen found. The present invention therefore provides, in a first aspect,a compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

-   R₁ is hydrogen, hydroxy, fluoro, chloro, C₁₋₆alkyl, C₃₋₇cycloalkyl,    C₃₋₇cycloalkyloxy, C₁₋₆alkoxy or haloC₁₋₆alkoxy;-   m is 0 when    is a double bond and m is 1 when    is a single bond;-   R₂ is hydrogen, halogen, cyano, nitro, C₁₋₆alkyl, C₃₋₇cycloalkyl,    C₃₋₇cycloalkyloxy, haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy,    C₁₋₆alkylthio, amino, mono- or di-C₁₋₆alkylamino or an N-linked 4 to    7 membered heterocyclic group;-   X is —(CH₂—CH₂)—, —(CH═CH)—, —(CH₂)₃—, —C(CH₃)₂—, —(CH═CH—CH₂)—,    —(CH₂—CH═CH)— or a group —(CHR₅)— wherein R₅ is hydrogen, halogen,    hydroxy, cyano, nitro, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyloxy,    haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy or C₁₋₆alkylthio;-   R₃ is halogen, cyano, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyloxy,    C₁₋₆alkoxy, C₁₋₆alkylthio, hydroxy, amino, mono- or    di-C₁₋₆alkylamino, an N-linked 4 to 7 membered heterocyclic group,    nitro, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, aryl, arylC₁₋₆alkyl,    arylC₁₋₆alkyloxy, arylC₁₋₆alkylthio or COOR₆, CONR₇R₈ or COR₉    wherein R₆, R₇; R₈ and R₉ are independently hydrogen or C₁₋₆alkyl;-   p is 0,1 or 2or 3;-   R₄ is hydrogen, halogen, hydroxy, cyano, nitro, C₁₋₆alkyl,    C₁₋₆alkanoyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyloxy, haloC₁₋₆alkyl,    C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₁₋₆alkylthio, amino, mono- or    di-C₁₋₆alkylamino or an N-linked 4 to 7 membered heterocyclic group;-   Y is oxygen, sulfur, —CH₂— or NR₁₀ wherein R₁₀ is hydrogen or    C₁₋₆alkyl;-   D is a single bond, —CH₂—, —(CH₂)₂— or —CH═CH—; and-   Z is an optionally substituted C-linked 4 to 7 membered heterocyclic    group containing at least one nitrogen, an optionally substituted    N-linked 4 to 7 membered heterocyclic group, or Z is —NR₁₁R₁₂ where    R₁₁ and R₁₂ are independently hydrogen or C₁₋₆alkyl.

The following terms, whether used alone or as part of another group areto be given the following meanings, unless otherwise stated.

The term “halogen” and its abbreviated form “halo” are used herein todescribe fluorine, chlorine, bromine or iodine.

The term “alkyl” is used herein to describe a straight chain or branchedfully saturated hydrocarbon group. “C₁₋₆alkyl” refers to alkyl groupshaving from one to six carbon atoms, including all isomeric forms, suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, neopentyl, sec-pentyl, n-pentyl, isopentyl,tert-pentyl and hexyl.

The term “C₁₋₆alkanoyl” refers to an alkanoyl group having from 1 to 6carbon atoms, such as methanoyl (or “formyl”), ethanoyl (or “acetyl”),propanoyl, isopropanoyl, butanoyl, isobutanoyl, sec-butanoyl, pentanoyl,neopentanoyl, sec-pentanoyl, isopentanoyl, tertpentanoyl and hexanoyl.

The term “C₁₋₆alkoxy” refers to a straight chain or branched chainalkoxy (or “alkyloxy”) group having from one to six carbon atoms,including all isomeric forms, such as methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy,neopentoxy, sec-pentoxy, n-pentoxy, isopentoxy, tert-pentoxy and hexoxy.

The term “C₃₋₇cycloalkyl” refers to a cycloalkyl group consisting offrom 3 to 7 carbon atoms, such as cyclopropane, cyclobutane,cyclopentane, cyclohexane and cycloheptane. Optional substituents forC₃₋₇cycloalkyl includes one or more halogen, hydroxy, oxo, C₁₋₆alkyl,cyano, CF₃, OCF₃, C₁₋₆alkoxy and C₁₋₆alkanoyl.

The term “C₁₋₆alkylthio” refers to a straight chain or branched chainalkylthio group having from one to six carbon atoms, such as methylthio,ethylthio, propylthio, isopropylthio, butylthio, isobutylthio,sec-butylthio, tert-butylthio, pentylthio, neopentylthio,sec-pentylthio, n-pentylthio, isopentylthio, tert-pentylthio andhexylthio.

The term “mono- or di-C₁₋₆alkylamino” refers to an amino group which issubstituted by one C₁₋₆alkyl group or an amino group which issubstituted by two C₁₋₆alkyl groups, the two amino groups being the sameor different. Examples of monoC1-6alkylamino include methylamine,ethylamine, propylamine, isopropylamine, butylamine, isobutylamine,sec-butylamine, tert-butylamine, pentylamine, neopentylamine,sec-pentylamine, n-pentylamine, isopentylamine, tert-pentylamine andhexylamine. Examples of di-C1-6alkylamino include dimethylamine,diethylamine, dipropylamine, diisopropylamine, dibutylamine,diisobutylamine, disec-butylamine, ditert-butylamine, dipentylamine,dineopentylamine, dihexylamine, butylmethylamino, isopropylmethylamino,ethylisopropylamino, ethylmethylamino, etc.

The term “aryl” is used herein to describe groups such as phenyl ornaphthyl, which may be optionally substituted by one or more ofC₁₋₆alkyl (to form “arylC₁₋₆alkyl”), halogen, CF₃ or C₁₋₆alkoxy (to form“arylC₁₋₆alkoxy”).

The terms “halo C₁₋₆alkoxy” or “haloC₁₋₆alkyl” are used to describe aC₁₋₆alkoxy or a C₁₋₆alkyl group, respectively, substituted with one ormore halogens. Examples include —CHCl₂, —CF₃, —OCF₃, etc.

The term “heterocyclic group” is used herein to describe a stablearomatic or non-aromatic ring containing 1, 2 or 3 heteroatoms selectedfrom nitrogen, sulphur and oxygen. Suitable examples of 4 to 7 memberedheterocyclic groups include azetidinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, oxazolinyl, isothiazolidinyl, thiazolidinyl, pyrrolyl,pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, isothiazolyl, thiazolyl,piperidyl, piperazinyl, morpholinyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, azepinyl, azepanyl, dioxolanyl, thienyl, tetrahydrothienyl,tetrahydrofuryl, dioxanyl and dithianyl.

The term “N-linked heterocyclic group” is used herein to describe aheterocyclic group which is linked to the remainder of the molecule viaa nitrogen atom. Suitable examples of 4 to 7 membered N-linkedheterocyclic groups include azetidinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, oxazolinyl, isothiazolidinyl, thiazolidinyl, pyrrolyl,pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, piperidyl, piperazinyl,morpholinyl and azepanyl.

The term “C-linked heterocyclic group containing at least one nitrogen”is used herein to describe a heterocyclic group which Is contains atleast one nitrogen atom and is linked to the remainder of the moleculevia a carbon atom. Suitable examples of 4 to 7 membered C-linkedheterocyclic groups containing at least one nitrogen include azetidinyl,pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolyl, pyrrolinyl,pyrazolinyl, imidazolyl, pyrazolyl, piperidyl, piperazinyl, morpholinyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, azepinyl and azepanyl.

More than one optional substituent may be present in the N-linked orC-linked heterocyclic group, which may be the same or different, and maybe attached to any carbon atom of the heterocyclic group or an availablenitrogen atom.

Suitable optional substituents for the N-linked or C-linked heterocyclicgroup include C₁₋₆alkyl, amino, mono- or di-C₁₋₆alkylamino, aryl,arylC₁₋₆alkyl, arylamino, hydroxy, C₁₋₆alkylamido, hydroxyC₁₋₆alkyl,C₁₋₆alkoxycarbonyl, halogen, haloC1-6alkyl, a heteroaromatic group (suchas indole or benzimidazole), an aromatic or non-aromatic N-linked orC-linked heterocyclic group or an aromatic or non-aromaticheterocycleC₁₋₆alkyl optionally substituted by C₁₋₆alkyl. Examples ofaromatic or non-aromatic heterocycleC₁₋₆alkyl include heterocycle-methyl(such as pyridinyl-methyl and benzimidazolyl-methyl) andheterocycle-ethyl (such as morpholinyl-ethyl and indolyl-ethyl).

Substituents in the N-linked or C-linked heterocyclic group may form abridge structure, to form a group such as for example2-oxa-5-azabicyclo[2.2.1]heptyl. Such a bicyclic group may be furthersubstituted by the substituents listed above. More than one substituentmay be present on the same carbon atom to form spiro structures such as1,4 and 1,5 dioxa Spiro compounds.

When X is a group —(CHR₅)—, preferably R₅ is hydrogen. Preferably X is—CH₂—.

When

is a single bond, preferably R₁ is hydrogen, hydroxy or C₁₋₆alkoxy.

Preferably R₂ is hydrogen.

When p is 2 or 3, R₃ may be the same or different. Preferably p is 1 or2 and R₃ is/are halogen, particularly chloro or fluoro, attached at the3 or the 3,4-positions of the phenyl ring.

Preferably R₄ is C₁₋₆alkoxy (particularly methoxy), OCF₃, halogen orcyano.

Preferably Y is oxygen.

Preferably D is —CH₂—.

Preferably Z is an optionally substituted N-linked 4 to 7 memberedheterocyclic group, in particular piperidyl. Preferred substituentsinclude halogen (particularly fluoro) and C₁₋₆alkyl (particularlymethyl).

Preferred compounds are compounds of formula (Ia):

wherein R₃, p, R₄, Y, D, Z,

are as defined for formula (I) and X₁ is —CH₂— or —HC(OH)—. Preferredfeatures of formula (I) also apply to formula (Ia).

Preferred compounds include:

-   1.    3-(3,4-Dichloro-phenyl)-3-hydroxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl)]-pyrrolidin-2-one-   2.    3-(3,4-Dichloro-phenyl)-3-hydroxy-1-[4-methoxy-3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrrolidin-2-one-   3.    3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one-   4.    1-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-pyrrolidin-2-one-   5.    1-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-3-hydroxy-pyrrolidin-2-one-   6.    3-(3,4-Dichloro-phenyl)-1-(4-methoxy-3-[2-(4methyl-piperidin-1-yl)-ethoxy]-phenyl)-pyrrolidin-2-one-   7.    3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one-   8.    3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-morpholin-4-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one-   9.    1-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-1,5-dihydro-pyrrol-2-one-   10.    3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one-   11.    3-(3-Fluoro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one-   12.    3-(3,4-Dichloro-phenyl)-1-(-3-[2-(4,4-difluoro-piperidin-1-yl)-ethoxy]-4-methoxy-phenyl)-1,5-dihydro-pyrrol-2-one-   13.    3-(3-Fluoro-phenyl)-5-hydroxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one-   14.    1-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-5-hydroxy-pyrrolidin-2-one-   15.    3-(3,4-Dichloro-phenyl)-1-(-3-[2-(4,4-difluoro-piperidin-1-yl)ethoxy]-4-methoxy-phenyl)-5-hydroxy-pyrrolidin-2-one-   16.    3-(3-Fluoro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one-   17.    3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one-   18.    3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-methyl-pyrrolidin-2-one-   19.    3-(3-Chloro-phenyl)-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-1,5-dihydro-pyrrol-2-one-   20.    3-(3,4-Dichloro-phenyl)-1-[4methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H-pyridin-2-one-   21.    3-(3,4-Dichloro-phenyl)-1-[4methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-piperidin-2-one-   22.    3-(3,4-Dichloro-phenyl)-1-(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-3,4-dihydro-pyrrol-2-one-   23.    3-(3,4Dichloro-phenyl)-1-(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-4-methyl-1,5-dihydro-pyrrol-2-one-   24.    3-(4-Chloro-phenyl)-1-(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-3,4-dihydro-pyrrol-2-one-   25.    3-(4Chloro-phenyl)-1-(4-methoxy-3-[2-piperidin-1-yl)-ethoxy]-phenyl)-3,4-dihydro-pyrrol-2-one-   26.    3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(piperidin-3-ylmethoxy)-phenyl]-pyrrolidin-one-   27.    3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(1-methyl-piperidin-3-ylmethoxy)-phenyl]-pyrrolidin-one-   28.    N-{4-[3-(3,4-dichlorophenyl)-2-oxo-2,5-dihydro-1H-pyrrol-1-yl]-2-[2-(1-piperidinyl)ethoxy]phenyl}acetamide-   29.    N-{4-[3-(3,4dichlorophenyl)-2-oxo-pyrrolidin-1-yl]-2-[2-(1-piperidinyl)ethoxy]phenyl}acetamide-   30.    3-(3,4-Dichloro-phenyl)-1-{4-methoxy-3-[2-(4methyl)-piperidin-1-yl-ethoxy]-phenyl}-3-methyl-pyrrolidin-2-one-   31.    3-(3-Chloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)phenyl]-pyrrolidin-2-one-   32.    3-(3-Trifluoromethyl-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)phenyl]-pyrrolidin-2-one-   33.    3-(3-Trifluoromethyl-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)phenyl]-1,5    dihydro-pyrrol-2-one-   34.    3-(3-Chloro-phenyl)-5-methoxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one-   35.    3-(3-Chloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one-   36.    3-(4Fluoro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one-   37.    3-(4Fluoro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one-   38.    1-{4-Methoxy-3-[2-(4methyl-piperidin-1-yl)ethoxy]-phenyl}-3-(4methyl-phenyl)-1,5-dihydro-pyrrol-2-one-   39.    1-{4-Methoxy-3-[2-(piperidin-1-yl)-ethoxy]-phenyl}-3-(4-methyl-phenyl)-1,5-dihydro-pyrrol-2-one-   40.    3-(4-Bromo-phenyl)-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-1,5-dihydro-pyrrol-2-one-   41.    1-{4-Methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-3-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one-   42.    3-(2-Chloro-phenyl)-1-{4-methoxy-3-[2-(4methyl-piperidin-1-yl)-ethoxy]-phenyl}-1,5-dihydro-pyrrol-2-one-   43.    3-(3,4-Dichloro-phenyl)-3-hydroxy-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-pyrrolidin-2-one-   44.    3-(3,4-Dichloro-phenyl)-3-fluoro-1-{4methoxy-3-[2-(4methyl-piperidin-1-yl)-ethoxy]-phenyl}-pyrrolidin-2-one-   45.    3-(3,4Dichloro-phenyl)-1-{4-methoxy-3-[(1-methyl-pyrrolidin-2-yl)-methoxy]-phenyl}-pyrrolidin-2-one-   46.    3-(3,4-Dichloro-phenyl)-1-{4-methoxy-3-[(1-methyl-pyrrolidin-2-yl)-methoxy]-phenyl}-3,4-dihydro-pyrrol-2-one    and pharmaceutically acceptable salts thereof.

The compounds of formula (I) can form acid addition salts. It will beappreciated that for use in medicine the salts of the compounds offormula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include those described in J. Pharm. Sci., 1977, 66, 1-19,such as acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.

The compounds of this invention may be in crystalline or non-crystallineform, and, if crystalline, may optionally be hydrated or solvated. Thisinvention includes within its scope stoichiometric hydrates as well ascompounds containing variable amounts of water.

Certain compounds of formula (I) are capable of existing instereoisomeric forms (e.g. geometric or (“cis-trans”) isomers,diastereomers and enantiomers) and the invention extends to each ofthese stereoisomeric forms and to mixtures thereof including racemates.The different stereoisomeric forms may be separated one from the otherby the usual methods, or any given isomer may be obtained bystereospecific or asymmetric synthesis. The invention also extends toany tautomeric forms and mixtures thereof.

The present invention also provides a process for the preparation of acompound of formula (I) or a pharmaceutically acceptable salt thereof,which process comprises:

-   (a) reacting a compound of formula (II):    wherein R₁, R₂, R₃, R₄, m, p, X,    Y and D are as defined for formula (I), and L is a leaving group,    with a compound of formula (Ill):    Z-H   (III)    wherein Z is as defined for formula (I); or-   (b) cyclising a compound of formula (IV):    wherein R₁, R₂, m, R₃, p, R₄, Y, D, Z and    are as defined for formula (I) and G is a group —X═CH₂, wherein X is    as defined for formula (I), dehydrogenated as required;-   optionally followed by:    -   removing any protecting groups; and/or    -   converting a compound of formula (I) into another compound of        formula (I); and/or    -   forming a pharmaceutically acceptable salt.

For the reaction of process (a), suitably L is mesylate. The reactionmay take place in a solvent such as DMF In the presence of sodium iodideand potassium carbonate.

The reaction of process (b) suitably takes place in a solvent such asTHF in the presence of OsO₄ and NalO₄.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard techniques. For example, and by way ofillustration rather than limitation, a compound wherein X is —(HCOH)—may be converted to a compound wherein X is —(CH₂)— by using a suitablereducing agent such as triethylsilane-trifluoroacetic acid usingdichloromethane as solvent, and a compound wherein R₁ is hydroxy may beconverted to compound wherein m is 0 and

is a double bond by an elimination reaction in TFA.

Compounds of formulae (II), (III) and (IV) are commercially available ormay be prepared according to methods described herein or may be preparedaccording to known methods or by analogous methods thereto.

Those skilled in the art will appreciate that it may be necessary toprotect certain groups to carry out the above processes. Suitableprotecting groups and methods for their attachment and removal areconventional in the art of organic chemistry, such as those described inGreene T. W. ‘Protective groups in organic synthesis’ New York, Wiley(1981).

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier orexcipient.

In a further aspect, the present invention provides a process forpreparing a pharmaceutical composition, the process comprising mixing acompound of formula (I) or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier or excipient.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); tabletting lubricants lubricants (e.g.magnesium stearate, talc or silica); disintegrants (e.g. potato starchor sodium starch glycollate); and acceptable wetting agents (e.g. sodiumlauryl sulphate). The tablets may be coated according to methods wellknown in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents (e.g. sorbitol) syrup,cellulose derivatives or hydrogenated edible fats), emulsifying agents(e.g. lecithin or acacia), non-aqueous vehicles (which may includeedible oils e.g. almond oil, oily esters, ethyl alcohol or fractionatedvegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoatesor sorbic acid), and, if desired, conventional flavourings or colorants,buffer salts and sweetening agents as appropriate. Preparations for oraladministration may be suitably formulated to give controlled release ofthe active compound.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. Formulations for injection may bepresented In unit dosage form e.g. in ampoules or in multi-dose,utilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle, optionally with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use. The compound, depending on the vehicle and concentrationused, can be either suspended or dissolved in the vehicle. In preparingsolutions, the compound can be dissolved for injection and filtersterilised before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are dissolved in the vehicle. To enhance the stability,the composition can be frozen after filling into the vial and the waterremoved under vacuum. Parenteral suspensions are prepared insubstantially the same manner, except that the compound is suspended inthe vehicle instead of being dissolved, and sterilisation cannot beaccomplished by filtration. The compound can be sterilised by exposureto ethylene oxide before suspension in a sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device. Thuscompounds of formula (I) may be formulated for oral, buccal, parenteral,topical (including ophthalmic and nasal), depot or rectal administrationor in a form suitable for administration by inhalation or insufflation(either through the mouth or nose).

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

The compounds of the present invention have affinity for the 5-HT_(2C)receptor. The affinity can be determined by assessing their ability todisplace [³H]-mesulergine from rat or human 5-HT_(2C) clones expressedIn 293 cells in vitro, as described in WO 94/04533.

All the Example compounds were tested according to this assay and werefound to have pKi values >5.8. Some compounds show a considerably higheraffinity in the range of 7.0 to >9.0 in human cells.

The intrinsic activity of the compounds of this invention can bedetermined according to the [³⁵S]GTP_(γ)S functional assay which isdescribed in WO 99/07700.

Compounds of formula (I) and their pharmaceutically acceptable salts areof use in the treatment of certain CNS disorders such as depression(which term is used herein to include bipolar depression, unipolardepression, single or recurrent major depressive episodes with orwithout psychotic features, catatonic features, melancholic features,atypical features or postpartum onset, seasonal affective disorder,dysthymic disorders with early or late onset and with or withoutatypical features, neurotic depression and social phobia, depressionaccompanying dementia for example of the Alzheimer's type, vasculardementia with depressed mood, schizoaffective disorder or the depressedtype, and depressive disorders resulting from general medical conditionsincluding, but not limited to, myocardial infarction, diabetes,miscarriage or abortion, etc), anxiety including generalised anxiety andsocial anxiety disorder, schizophrenia, panic disorder, agoraphobia,social phobia, epilepsy, obsessive compulsive disorder andpost-traumatic stress disorder, pain (particularly neuropathic pain),migraine, memory disorders, including dementia, amnesic disorders andage-associated memory impairment, disorders of eating behavioursincluding anorexia nervosa and bulimia nervosa, sexual dysfunction,sleep disorders (including disturbances of circadian rhythm, dyssomnia,insomnia, sleep apnea and narcolepsy), withdrawal from abuse of drugssuch as of cocaine, ethanol, nicotine, benzodiazepines, alcohol,caffeine, phencyclidine (phencyclidine-like compounds), opiates (e.g.cannabis, heroin, morphine), sedative ipnotic, amphetamine oramphetamine-related drugs (e.g. dextroamphetamine, methylamphetamine) ora combination thereof, Alzheimer's disease, motor disorders such asParkinson's disease, dementia in Parkinson's disease,neuroleptic-induced Parkinsonism and tardive dyskinesias, as well asother psychiatric disorders, disorders associated with spinal traumaand/or head injury such as hydrocephalus, gastrointestinal disorderssuch as IBS (Irritable Bowel Syndrome), Crohn's disease, ulcerativecolitis, non-steroidal anti-inflammatory drug induced damage) as well asmicrovascular diseases such as macular oedema and retinopathy.

It is to be understood that, as used herein, the term “treatment” refersto alleviation of established symptoms as well as prophylaxis.

Thus the present invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance. In particular, the present invention provides a compound offormula (I) or a pharmaceutically acceptable salt thereof for use in thetreatment of the above disorders. In particular the invention provides acompound of formula (I) or a pharmaceutically acceptable salt thereoffor use as a therapeutic substance In the treatment of a CNS disorder.Preferably the CNS disorder is depression or anxiety.

Compounds of the invention may be administered in combination with otheractive substances such as 5HT3 antagonists, NK-1 antagonists, serotoninagonists, selective serotonin reuptake inhibitors (SSRI), noradrenalinere-uptake inhibitors (SNRI), tricyclic antidepressants and/ordopaminergic antidepressants.

Suitable 5HT3 antagonists which may be used in combination of thecompounds of the inventions include for example ondansetron,granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbine,metoclopramide.

Suitable SSRIs which may be used in combination with the compounds ofthe invention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compounds ofthe invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention include imipramine, amitriptiline,chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combinationwith a compound of the invention include bupropion and amineptine.

It will be appreciated that the compounds of the combination orcomposition may be administered simultaneously (either in the same ordifferent pharmaceutical formulations), separately or sequentially.

The invention further provides a method of treatment of the abovedisorders in mammals including humans, which comprises administering tothe sufferer a therapeutically safe and effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof. Inparticular the invention provides a a method of treatment of a CNSdisorder in mammals including humans, which comprises administering tothe sufferer a therapeutically safe and effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof. Preferablythe disorder is depression or anxiety.

In another aspect, the invention provides for the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for use in the treatment of the abovedisorders. In particular the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof inthe manufacture of a medicament for use in the treatment of a CNSdisorder. Preferably the CNS disorder is depression or anxiety.

The composition of the present invention may contain from 0.1% to 99% byweight, preferably from 10 to 60% by weight, of the active material,depending on the method of administration. The dose of the compound usedin the treatment of the aforementioned disorders will vary in the usualway with the seriousness of the disorders, the weight of the sufferer,and other similar factors. However, as a general guide suitable unitdoses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unitdoses may be administered more than once a day, for example two or threetimes a day. Such therapy may extend for a number of weeks or months.When administered in accordance with the invention, no unacceptabletoxicological effects are expected with the compounds of the invention.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Descriptions and Examples illustrate the preparation ofcompounds of the present invention.Preparation 1: 1-Benzyl-4,4-difluoro-piperidine

Procedure:

Chem. Pharm. Bull. 1993, 41, 11, 1971.

NMR (¹H, CDCl₃): δ 7.4-7.25 (m, 5H), 3.55 (s, 2H), 2.54 (m, 4H), 1.99(m, 4H). MS (m/z):212 [MH]⁺Preparation 2: 4,4-Difluoro-piperidine Hydrochloride

Procedure:

Chem. Pharm. Bull. 1993, 41, 11, 1971.

NMR (¹H, DMSO-d6): δ 9.22 (bs, 2H), 3.20 (m, 4H), 2.25 (m, 4H). MS(m/z): 122 [MH-HCl]⁺Preparation 3: 2-Chloro-1-(4,4-difluoro-piperidin-1-yl)-ethanone

Procedure:

To a solution of 4,4-difluoro-piperidine hydrochloride (1120 mg, 7.13mmol) in anh. CH₂Cl₂ (10 ml) was added, at 0° C. and. under N₂, TEA (2.5eq, 2.18 ml) and chloroacetyl chloride (1.1 eq, 661 μl). The reactionwas stirred at room temperature for 1 hour. The solution was dilutedwith water (30 ml) and extracted with ethyl acetate (3×25 ml). Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness in vacuo to give 1128 mg of the title product(yield: 80.3%).

NMR (¹H, DMSO-d6): δ 4.44 (s, 2H), 3.55 (m, 4H), 2.0 (m, 4H). MS (m/z):198 [MH]⁺, 1ClPreparation 4: 2-Chloro-5-nitro-phenol

Procedure:

J. Chem. Soc. 1896, 69,1326.

NMR (¹H, DMSO-d6): δ 11.3 (s, 1H), 7.75 (d, 1H), 7.66 (d, 1H), 7.64 (s,1H).Preparation 5: Acetic Acid 2-(2-methoxy-5-nitro-phenoxy)-ethyl Ester

Procedure:

To a solution of 2-methoxy-5-nitro-phenol (2202 mg, 13.02 mmol) inacetone (110 ml), under N₂, was added K₂CO₃ (4.45 eq., 8000 mg) and2-bromoethyl acetate (2.1 eq, 3 ml). The mixture was heated to refluxfor 20 hours, filtered and then concentrated in vacuo. The crude productwas triturated with AcOEt/cHex 1/1 (70 ml) to give 2999 mg of the titleproduct as a white solid (90.2%, mp: 120-121.3° C.).

NMR (¹H, CDCl₃): δ 7.9 (dd, 1H), 7.75 (d, 1H), 6.9 (d, 1H), 4.45 (m,2H), 4.3 (m, 2H), 3.95 (s, 3H), 2.05 (s, 3H).Preparation 6: 1-[2-(2-Methoxy-5-nitro-phenoxy)-ethyl]-piperidine

Procedure:

To a solution of 2-methoxy-5-nitrophenol (1.5 g, 8.87 mmol) in DMF (18ml) at room temperature were added K₂CO₃ (2.70 g, 19.52 mmol) and(1-(2-chloroethyl)piperidin hydrochloride) (1.79 g, 9.75 mmol). Thesuspension was stirred at room temperature for 24 hours. The suspensionwas diluted with water (20 ml) and extract with EtOAc (2×20 ml), thecombined organic phases were dried over Na₂SO₄, filtered andconcentrated to dryness in vacuo, to obtain the title product as ayellow oil.

NMR (¹H, CDCl₃): δ 7.85 (dd, 1H), 7.75 (d, 1H), 6.90 (d, 1H), 4.20 (t,2H), 3.90 (s, 3H), 2.80 (t, 2H), 2.45-2.60 (m, 4H), 1.55-1.65 (m, 4H)(m, 4H), 1.35-1.50 (m, 2H).

MS (m/z): 281[MH]⁺.Preparation 7:1-(4,4-Difluoro-piperidine-1-yl)-2-(2-methoxy-4-nitro-phenoxy)-ethanone

Procedure:

2-Methoxy-nitro-phenol (177 mg, 1.05 mmol), was dissolved in dry DMF (2ml) under N₂. Potassium carbonate (158 mg, 1.1 eq) was added and themixture was stirred for 15 min, then2-chloro-1-(4,4-difluoro-piperidin-1-yl)-ethanone (228 mg, 1.1 eq)dissolved in dry DMF (3 ml) was added. After 20 hours a saturatedsolution of NH₄Cl was added and the mixture extracted with CH₂Cl₂ (2×25ml). The organic phase was washed with NaOH 0.1 N (50 ml), water (50ml), dried over Na₂SO₄ and concentrated in vacuo to give 405 mg of crudetitle product (mp 127-130° C.) that was utilized without furtherpurification.

NMR (¹H, CDCl₃): δ 7.98 (dd, 1H), 7.77 (d, 1H), 6.96 (d, 1H), 4.84 (s,2H), 3.98 (s, 3H), 3.8-3.65 (m, 4H), 2.15-1.95 (m, 4H). MS (m/z): 331[MH]⁺.Preparation 8: 1-[2-(2-Chloro-5-nitro-phenoxy)-ethyl]-piperidine

NMR (¹H, CDCl₃): δ 7.84 (d, 1H), 7.81 (dd, 1H), 7.52 (d, 1H), 4.30 (t,2H), 2.92 (t, 2H), 2.6 (m, 4H), 1.5-1.7 (m, 6H). MS (m/z): 285 [MH]⁺,1Cl.Preparation 9: Acetic Acid 2-(5-amino-2-methoxy-phenoxy)-ethyl Ester

Procedure:

To a suspension of acetic acid 2-(2-methoxy-5-nitro-phenoxy)-ethyl ester(2904 mg, 11.38 mmol) in methanol (85 ml) was added, under N₂, ammoniumformate (5.4 eq, 3900 mg) and Pd/C 10% (cat, 1100 mg). The reaction wasstirred at room temperature for 1.5 hours, then filtered on celite padand concentrated to dryness in vacuo. The crude product was thendissolved in CH₂Cl₂ (50 ml) and the organic phase was washed with brine(2×30 ml) and water (1×30 ml). The combined organic extracts were driedover anhydrous Na₂SO₄ filtered and concentrated to dryness in vacuo.Flash chromatography of the crude product (silica gel, cHex/AcOEt 4/6)gave 2299 mg of the title product as a white foam (yield: 89.7%).

NMR (¹H, CDCl₃): δ 6.7 (dd, 1H), 6.3 (d, 1H), 6.25 (dd, 1H), 4.4 (m,2H), 4.15 (m, 2H), 3.75 (s, 3H), 2.05 (s, 3H). MS (m/z): 226.3 [MH]⁺.Preparation 10: 4-Methoxy-3-(2-piperidin-1-yl)-ethoxy-phenylamineHydrochloride

Procedure:

To a solution of the compound of Preparation 6 (2.30 g, 8.21 mmol) inMeOH (43.18 ml) were added a solution of NH₄Cl (5 eq, 2.20 g) in H₂O(36.83 ml) and iron (3 eq, 1.38 g). After stirring at reflux for 3hours, the solution was concentrated in vacuo and the crude was trituredwith CH₂Cl₂ to obtain 1.82 g of th title compound as a brown gum (yield:76%).

(¹H, DMSO-d6): δ 10.4-10.0 (broad, 1H), 6.72 (d, 1H), 6.34(d, 1H), 6.20(dd, 1H), 5.4-5.0 (broad, 2H), 4.24 (t, 2H), 3.64 (s, 3H), 3.52 (bs,2H), 3.42 (t, 2H), 3.00 (bs, 2H), 1.9-1.3 (bs, 6H). MS (m/z): 251[MH]⁺.Preparation 11: 4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenylamine

Procedure:

To a solution of 1-[2-(2-chloro-5-nitro-phenoxy)ethyl]-piperidine (782mg, 2.75 mmol) in MeOH (8 ml) were added a solution of NH₄Cl (5 eq, 735mg) in H₂O (8 ml) and iron (3 eq, 457 mg). After stirring at reflux for12 hours, the solution was concentrated in vacuo and chromatographatedover silica gel (CH₂Cl₂/MeOH 85/15) to give 757 mg of the title productas a green foam (yield: 87%).

NMR (¹H, CD₃OD): δ 7.0 (d, 1H), 6.4 (d, 1H), 6.2 (dd, 1H), 4.25 (t, 2H),3.35 (t, 2H), 3.25 (s, 2H), 3.15 (m, 4H), 1.8-1.5 (m, 6H). MS (m/z): 255[MH]⁺, 1Cl.Preparation 12: 2-(3,4-Dichloro-phenyl)-pent-4-enoic Acid

Procedure:

A solution of 3,4dichloro-phenylacetic acid (1.47 g, 7.17 mmol) in anh.THF (21 ml), under N₂, was treated with lithium bis(trimethylsilyl)amide (1M solution in THF, 2.2 eq., 16 ml) at −78° C. for 30 minutesbefore allyliodide(1.65 eq., 1.1 ml) was added. The mixture was stirredfor 3 hours at room temperature and quenched with water (20 ml). Thereaction mixture was acidified to pH=4 with HCl 1N. The product wasextracted with ethyl acetate (2×15 ml) and the organic phase was washedwith brine (1×15 ml), dried over Na₂SO₄ and concentrated in vacuo. Thecrude product was purified by flash chromatography (silica gel,AcOEt/cHex 2/8) to give 1137 mg of the title product as a pale yellowsolid (81%).

NMR (¹H, CDCl₃): δ 7.4 (m, 2H), 7.15 (dd, 1H), 5.7 (m, 1H), 5.05 (m,2H), 3.6 (t, 1H), 2.8 (m, 1H), 2.5 (m, 1H). MS (m/z): 244 [MH]⁺ +2Cl.Preparation 13: 2-(3-Fluoro-phenyl)-pent-4-enoic Acid

Procedure:

To a solution of 3-fluorophenylacetic acid (1.0 g, 6.49 mmol) in THF (10mL), at −78° C. was added lithium bis(trimethylsilyl)amide (14.28 mmol).To solution was stirred at this temperature for 30 min and allyl bromide(0.84 mL. 9.74 mmol) was added. The solution was stirred at roomtemperature for 3 hours. Then the solution ws diluted with water,acidified with HCl 2 N and extracted with EtOAC (3×). The combinedorganic phases were dried over anhydrous Na₂SO₄ filtered andconcentrated to dryness in vacuo. Flash chromatography of the crudeproduct (silica gel, cHex/AcOEt 7/3) gave 1.120 g of the title product(yield=89%, mp=49° C.)

NMR (¹H, DMSO-d6): δ 12.50 (bs, 1H), 7.35 (m, 1 H), 7.00-7.25 (m, 3H),5.60-5.80 (m, 1H), 4.90-5.10 (m, 1H), 3.65 (t, 1H), 2.60-2.70 (m, 1H),2.35-2.50 (m, 1H).Preparation 14: Acetic Acid2-(5-[2-(3,4-dichloro-phenyl)-pent-4-enoylamine]-2-methoxy-phenoxy)-ethylEster

Procedure:

To a solution of 2-(3,4-dichloro-phenyl)-pent-4-enoic acid (222.4 mg,0.907 mmol) in anh. CH₂Cl₂ (4 ml), under N₂, was added, at 0° C., oxalylchloride (1.9 eq., 0.15 ml) and DMF (cat). The reaction was stirred at0° C. for 15′ and at room temperature for 18 hours. The reaction mixturewas concentrated to dryness in vacuo and the crude intermediate was thendissolved, under N₂, in anh. CH₂Cl₂ (5 ml). Acetic acid2-(5-amino-2-methoxy-phenoxy)-ethyl ester (VVSI/6002/42/1) (1.22 eq, 250mg) and TEA (2 eq., 0.25 ml) were added to the reaction mixture at 0° C.The reaction was stirred at 0° C. for 15′ and at room temperature for 18hours. The reaction mixture was concentrated to dryness in vacuo Thecrude intermediate was then dissolved in CH₂Cl₂ and the organic phasewas washed with NH₄Cl sat (2×10 ml) and brine (2×10 ml). Flashchromatography of the crude product (silica gel, cHex/AcOEt 7/3) gave259 mg of the title product as a white (yield: 63.1%, mp: 112.7-114.2)

NMR (¹H, DMSO-d6): δ 10.02 (s, 1H), 7.60 (m, 2H), 7.36 (dd, 1H), 7.29(d, 1H), 7.07 (dd, 1H), 6.88 (d, 1H), 5.70 (m, 1H), 5.07 (m, 1H), 4.98(m, 1H), 4.30 (t, 2H), 4.09 (t, 2H), 3.74 (m, 1H), 3.70 (s, 3H), 2.75(m, 1H), 2.45 (m, 1H), 2.02 (s, 3H) MS (m/z): 452 [MH]⁺+2Cl mp:112.7-114° C.Preparation 15: Acetic Acid2-(5-[2-(3-fluoro-phenyl)-pent-4-enoylamino]-2-methoxy-phenoxy)-ethylEster

NMR (¹H, CDCl₃): δ 7.36 (d, 1H), 7.34 (m, 1H), 7.15 (d, 1H), 7.10 (dd,1H), 7.04 (bs, 1H), 7.00 (m, 1H), 6.77-6.84 (m, 1H), 5.74 (m, 1H),5.00-5.14 (m, 2H), 4.42 (t, 2H), 4.22 (t, 2H), 3.82 (s, 3H), 3.51 (t,1H), 2.96 (m, 1H), 2.58 (m, 1H), 2.08 (s, 3H). MS (m/z):402 [MH]⁺. mp:108.7-109.3° C.Preparation 16: 2-(3,4-Dichloro-phenyl)-pent-4-enoic-acid[4-chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide

NMR (¹H, CD₃OD): δ 7.58 (d, 1H), 7.54 (d, 1H), 7.48 (d, 1H), 7.33 (dd,1H), 7.27 (d, 1H), 7.0 (dd, 1H), 5.77 (m, 1H), 5.15-5.0 (m, 2H), 4.23(t, 2H), 3.70 (t, 1H), 3.02 (t, 2H), 2.9 (m, 1H), 2.82 (m, 4H), 2.5 (m,1H), 1.69 (m, 4H), 1.54 (m, 2H). MS (m/z): 481 [MH] +3Cl.Preparation 17: 2-(3,4-Dichloro-phenyl)-pent-4-enoic Acid(3-[2-(4,4-difluoro-piperidin-1-yl)-ethoxy]-4-methoxy-phenyl)-amide

NMR (¹H, DMSO-d6): δ 9.96 (s, 1H), 7.57 (d, 1H), 7.55 (d, 1H), 7.32 (dd,1H), 7.25 (d, 1H), 7.01 (dd, 1H), 6.82 (d, 1H), 5.61 (m, 1H), 5.06-4.93(m, 2H), 3.96 (m, 2H), 3.72 (t, 1H), 3.65 (s, 3H), 2.72 (t, 2H), 2.56(t, 4H), 2.45 (m, 2H), 1.9 (m, 4H) MS (m/z): 513[MH]⁺+2Cl.Preparation 18: Acetic Acid2-(5-[3-(3,4-dichloro-phenyl)-5-hydroxy-2oxo-pyrrolidine-1-yl]-2-methoxy-phenoxy)-ethylEster

Procedure:

To a solution acetic acid2-(5-[2-(3,4-dichloro-phenyl)-pent-4-enoylamine]-2-methoxy-phenoxy)-ethylester (950 mg, 2.1 mmol) in acetone/H₂O 8/1 (37.5/4.6 ml) was addedN-methyl-morpholine-N-oxide (2 eq, 493 mg) and OsO₄ 4 wt % sol. in water(cat, 1 ml). The reaction was stirred at room temperature for 18 hoursand then quenched with 40 ml of Na₂SO₃ sat. After 15 minutes stirringthe diol was extracted with ethyl acetate (2×20 ml), dried over Na₂SO₄,filtered and concentrated to dryness in vacuo. The crude product wasthen dissolved in THF/H₂O 1/1 (20/20 ml) and potassium periodate (1.5eq, 673.7 mg) was added. The reaction was stirred at room temperaturefor 2 hours. The solution was diluted with water (10 ml) and extractedwith ethyl acetate (3×10 ml). The combined organic extracts were driedover anhydrous Na₂SO₄ filtered and concentrated to dryness in vacuo.Flash chromatography of the crude product (silica gel, cHex/AcOEt 5/15)gave 170 mg of one diastereoisomer of the title product, 227 mg of theother diastereoisomer, and 236 mg of a mixture of both as a white foam(yield: 66% in 2 steps)

(51-1)

NMR (¹H, DMSO-d6): δ 7.61 (d, 1H), 7.60 (d, 1H), 7.32 (dd, 1H), 7.26 (d,1H), 7.11 (dd, 1H), 6.98 (d, 1H), 6.44 (d, 1H), 5.60 (t, 1H), 4.31 (t,2H), 4.18 (t, 2H), 4.13 (t, 1H), 3.75 (s, 3H), 2.5-2.3 (m, 2H), 2.03 (s,3H).

MS (m/z): 454 [MH] +2Cl.

(51-3)

NMR (¹H, DMSO-d6): δ 7.68 (d, 1H), 7.63 (d, 1H), 7.41 (dd, 1H), 7.12 (d,1H), 6.89 (m, 2H), 6.52 (d, 1H), 5.66 (m, 1H), 4.31 (m, 2H), 4.13 (m,2H), 3.87 (dd, 1H), 3.75 (s, 3H), 2.9 (m, 2H), 2.02 (s, 3H), 1.9 (m,1H).Preparation 19: Acetic Acid2-(5-[3-(3,4-dichloro-phenyl)-2-oxo-pyrrolidine-1-yl]-2-methoxy-phenoxy)-ethylEster

Procedure:

To a solution of acetic acid2-(5-[3-(3,4dichloro-phenyl)-5-hydroxy-2-oxo-pyrrolidine-1-yl]-2-methoxy-phenoxy)-ethylester (46 mg, 0.101 mmol) and triethylsilane (1.5 eq, 24 μl) in CH₂Cl₂(1 ml) was added trifluoroacetic acid (10 eq, 120 μl) dropwise. Afterstirring for 2 hours at room temperature, the solution was concentratedin vacuo, and then the solution was diluted with water (10 ml) andextracted with ethylacetate (3×10 ml). The combined organic extractswere dried over anhydrous Na₂SO₄, filtered and concentrated to drynessin vacuo. The crude product was purified by trituration inether/petroleum ether 1/1 to give 30 mg of the title product as a whitesolid (yield: 69%) (mp: 113° C.)

NMR (¹H, DMSO-d6): δ 7.62 (d, 1H), 7.61 (d, 1H), 7.47 (d, 1H), 7.33 (dd,1H), 7.09 (dd, 1H), 6.98 (d, 1H), 4.30 (t, 2H), 4.14 (t, 2H), 3.99 (t,1H), 3.86 (m, 2H), 3.74 (s, 3H), 2.55-2.2 (m+m, 1H+1H), 2.02 (s, 3H). MS(m/z): 375 [MH]⁺, 2Cl.Preparation 20:3-(3,4-Dichloro-phenyl)-1-[3-(2-hydroxy-ethoxy)-4-methoxy-phenyl]-pyrrolidine-2-one

Procedure:

To a solution of acetic acid2-(5-[3-(3,4-dichloro-phenyl)-2-oxo-pyrrolidine-1-yl]-2-methoxy-phenoxy)-ethylester (524 mg, 1.19 mmol) in EtOH 95% (10 ml), at r.t, was addedLiOH.H₂O (2 eq., 100 mg). After stirring for 2 hours at roomtemperature, the solution was concentrated in vacuo, and then dilutedwith water (10 ml) and extracted with ethylacetate (3×10 ml). Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered andconcentrated to dryness in vacuo. to give 470 mg of the title product(yield: 99%).

NMR (¹H, DMSO-d6): δ 7.62 (s, 1H), 7.61 (d, 1H), 7.47 (d, 1H), 7.33 (dd,1H), 7.05 (dd, 1H), 6.96 (d, 1H), 4.82 (t, 1H), 3.99 (t, 1H), 3.92 (t,2H), 3.86 (m, 2H), 3.70 (t, 2H), 3.74 (s, 3H), 2.55-2.22 (m, 2H). MS(m/z): 396 [MH]⁺+ClPreparation 21: 2-(3-Fluoro-phenyl)-pent-4-enoic Acid[3-(2-hydroxy-ethoxy)-4-methoxy-phenyl]-amide

Procedure:

To a solution of a compound of Preparation 15 (0.15 g, 0.37 mmol) inMeOH (1 mL) and THF (1 mL) at 45° C. was added an aqueous solution ofKOH (5 M, 0.5 mL). After 15 min the mixture was cooled to 25° C. AqueousHCl (1 M, 3 mL) and EtOAc were added. The organic layer was collected,dried (MgSO₄), filtered and evaporated in vacuo to give the titlecompound (0.13 g, 0.36 mmol, 99%) as a colourless solid.

NMR (¹H, CDCl₃, 300 MHz): δ 7.27-7.40 (m, 2H), 6.93-7.15 (m, 4H),6.71-6.85 (m, 2H), 5.62-5.80 (m, 1H), 4.98-5.11 (m, 2H), 4.05-4.11 (m,2H), 3.86-3.90 (m, 2H), 3.80 (s, 3H), 3.50 (t, 1H), 2.90-3.02 (m, 1H),2.46-2.60 (m, 1H), 1.91 (bs, 1H+H₂O). MS (m/z): 360 [MH]⁺.Preparation 22: Methansulfonic Acid2-(5-[3-(3,4dichloro-phenyl)-2-oxo-pyrrolidin-1-yl]-2-methoxy-phenoxy)-ethylEther

Procedure:

To a solution of alcohol,3-(3,4-Dichloro-phenyl)-1-[3-(2-hydroxy-ethoxy)-4-methoxy-phenyl]-pyrrolidine-2-one(470 mg, 1.18 mmol) in anh. CH₂Cl₂ (15.6 ml), at 0° C., under N₂, wasadded Et₃N (5 eq., 822 μl) and CH₃SO₂Cl (2 eq., 180 μl). The reactionwas stirred at room temperature for 3 hours. The reaction mixture wasdiluted with water (20 ml) and extracted with AcOEt (3×25 ml). Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo concentrated to dryness in vacuo. to give 560 mgof the tile compound as a light yellow foam (yield: 99%).

NMR (¹H, DMSO-d6): δ 7.62 (m, 2H), 7.47 (d, 1H), 7.33 (dd, 1H), 7.13(dd, 1H), 7.00 (d, 1H), 4.52 (m, 2H), 4.00 (m, 1H), 3.87 (m, 2H), 3.76(s, 3H), 3.24 (s, 3H), 2.53 (m, 1H), 2.21 (m, 1H). MS (m/z): 474[MH]⁺+ClPreparation 23: Methanesulfonic Acid2-(5-[2-(3-fluoro-phenyl)-pent-4-enoylamino]-2-methoxy-phenoxy)ethylEster

Procedure:

To a partial solution of compound of Preparation 21 (0.13 g, 0.36 mmol)in DCM (2 mL) and THF (2 ml was added N,N-diisopropylethylamine (0.13mL) followed by methanesulfonyl chloride (0.037 mL) resulting incomplete dissolution of the starting material. After 1.5 h water wasadded with stirring. After an additional 3 min the mixture waspartitioned between aqueous HCl (1 M) and a 1:1 mixture of EtOAc andpetroleum ether (40-60° C.). The organic layer was washed (water, brine)and the solvents removed in vacuo to give the title product as aslightly yellow film (0.18 g, quant.) containing residual ethyl acetate.

NMR (¹H, CDCl₃, 300 MHz): δ 7.26-7.37 (m, 2H), 7.04-7.16 (m, 3H),6.94-7.02 (m, 1H), 6.73-6.84 (m, 2H), 5.65-5.80 (m, 1H), 4.97-5.11 (m,2H), 4.53-4.58 (m, 2H), 4.21-4.26 (m, 2H), 3.77 (s, 3H), 3.50 (t, 1H),3.13 (s, 3H), 2.87-3.00 (m, 1H), 2.48-2.57 (m, 1H). MS (m/z): 438 [MH]⁺.Preparation 24: 2-(3-fluoro-phenyl)-pent-4-enoic Acid[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide

NMR (¹H, CDCl₃): δ 7.25-7.35 (m, 1H), ), 7.10-7.20 (m, 3H), 6.85-7.00(m, 2H), 6.75 (d, 1H), 5.6-5.8 (m, 1H), 4.9-5.15 (m, 2H), 4.1-4.2 (m,3H), 3.80 (s, 3H), 3.5 (t, 1H), 2.90-3.05 (m, 2H), ), 2.6-2.75 (m, 2H),2.5-2.6 (m, 1H), 1.95-2.25 (m, 2H), 1.65-1.85 (m, 4H), 1.4-1.6 (m, 2H).MS (m/z): 427 [MH]⁺.Preparation 25:4,4-Difluoro-1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-piperidine

Procedure:

1-(4,4-Difluoro-piperidine-1-yl)-2-(2-methoxy-4-nitro-phenoxy)-ethanone(320 mg, 0.96 mmol) was dissolved in anh. THF (20 ml), 1M BH₃.THF (2.2eq, 2.4 ml) was added dropwise to the solution, and the mixture washeated at reflux for 5 hours. The solution was cooled to roomtemperature, CH₃OH (10 ml) was added, and the solvent was removed underreduced pressure. The residue was dissolved in CH₃OH (10 ml), 6N HCl (20ml) was added, and the solution was heated to reflux for 1 hour. TheCH₃OH was removed under reduced pressure and the remaining aqueoussolution was made basic (pH>10) with 2.5N NaOH. The basic solution wasextracted with ethyl acetate (3×20 ml). The combined organic extractswere dried over anhydrous Na₂SO₄ and the solvent was removed underreduced pressure to give 258 mg of the title product as a light yellowoil. (yield: 85%)

NMR (¹H. CDCl₃): δ 7.91 (dd, 1H), 7.77 (d, 1H), 6.89 (d, 1H), 4.19 (t,2H), 2.90 (t, 2H), 2.71 (m, 4H), 2.01 (m, 4H).Preparation 26:4-[2-(4,4Difluoro-piperidin-1-yl)-ethoxy]-3-methoxy-phenylamine

NMR (¹H, CDCl₃): δ 6.73 (d, 1H), 6.34 (d, 1H), 6.29 (dd, 1H), 4.18 (t,2H), 3.78 (s, 3H), 3.02 (t, 2H), 2.89 (bs, 4H), 2.13 (m, 4H).Preparation 27: 4-Methoxy-3-(2-pyrrolidin-1-yl-ethoxy)-phenylamine

The title compound (brown solid) was prepared in an analogous manner toPreparations 9 and 11 using 2-methoxy-5-nitrophenol and1-(2-chloroethyl)pyrrolidine hydrochloride.

NMR (¹H, CDCl₃): δ 6.70 (d, 1H), 6.30 (s, 1H), 6.20 (d, 1H), 4.08 (t,2H), 3.75 (s, 3H), 3.40 (bs, 2H), 2.90 (t, 2H), 2.65-2.55 (m, 4H),1.80-1.74 (m, 4H). MS (m/z): 237 [MH]⁺.Preparation 28: 2-(3,4-Dichloro-phenyl)-pent-4-enoic-acid[4-methoxy-3-(2-pyrrolidin-1yl-ethoxy)-phenyl]-amide

To a solution of 2-(3,4-dichloro-phenyl)-pent-4-enoic acid (0.19 g) indry CH₂Cl₂ (3 ml), under N₂, was added, at 0° C., oxalyl chloride (0.10ml) and DMF (cat). The reaction was allowed to warm to room temperature.After 1 h the reaction mixture was concentrated to dryness in vacuo. Tothis material was added a DMF (dry, 2 ml) solution of4-methoxy-3-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.22 g) which hadbeen converted to the hydrochloride salt by treatment with HCl/Et₂O (1eq.) followed by evaporation. The mixture was heated at 110° C. for 2 h,then partitioned between aqueous NaHCO₃ and EtOAc. The organic layer waswashed (brine), concentrated and purified by column chromatography(silica gel, CH₂Cl₂/MeOH/NH₃) to give the title compound (0.18 g) as anorange oil.

NMR (¹H, CDCl₃): δ 7.50-7.35 (m, 3H), 7.15 (s, 1H), 6.90 (d, 1H), 6.73(d, 1H), 5.77-5.62 (m, 1H), 5.10-4.96 (m, 2H), 4.15-4.05 (m, 2H), 3.80(s, 3H), 3.46 (t, 1H), 2.96-2.83 (m, 3H), 2.70-2.54 (m, 4H), 2.40 (bs,2H), 1.85-1.73 (m, 4H). MS (m/z): 463 [MH](⁺, 2Cl.Preparation 29:3-(3,4-Dichloro-phenyl)-5-hydroxy-1-[4-methoxy-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one

The title compound (colourless foam, ca. 1:1 mixture ofdiastereoisomers) was prepared from2-(3,4dichloro-phenyl)-pent-4-enoic-acid[4-methoxy-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide in an analogousmanner to the one described for Example 15.

NMR (¹H, CDCl₃): δ 7.44 (s, 0.5H), 7.28-7.12 (m, 2H), 7.06 (s, 0.5H),6.95-6.80 (m, 2H), 6.68 (d, 1H), 5.54-5.44 (m, 1H), 3.96-3.85 (m, 3H),3.67 (s, 3H), 3.60-3.53 (m, 0.5H), 3.78-3.70 (m, 2.5H), 2.47-2.18 (m,5.5H), 2.00-1.91 (m, 0.5H), 1.67-1.55 (m, 4H). MS (m/z): 465 [MH]⁺, 2Cl.Preparation 30: [4-Methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-aceticAcid 2-piperidin-1-yl-ethyl Ester

A mixture of (3-hydroxy-4-methoxy-phenyl)-acetic acid (1.85 g), dry DMF(25 ml), K₂CO₃ (5.9 g) and N-chloroethylpiperidine hydrochloride (3.74g) was heated at 40° C. for 5 h. Volatiles were then removed in vacuoand the residue partitioned between water and EtOAc. The organic layerwas washed (brine) and concentrated to give the title (3.76 g) compoundas an orange oil.

NMR (¹H, CDCl₃): δ 6.93-6.80 (m, 3H), 4.22 (t, 2H), 4.14 (t, 2H), 3.82(s, 3H), 3.55 (s, 2H), 2.82 (t, 2H), 2.66-2.40 (m, 10H), 1.66-1.40 (m,12H).Preparation 31: [4-Methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-aceticAcid Methyl Ester

[4-Methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-acetic acid2-piperidin-1-yl-ethyl ester (6.3 g) in MeOH (6 ml), THF (6 ml) andwater (6 ml) containing KOH (1.7 g) was heated at 45° C. for 1 h andthen allowed to cool to 25° C. over 90 min. With stirring in an ice bathconc. aqueous HCl (6 ml) was then added. The mixture was evaporated todryness. The material was heated at reflux with HCl in MeOH (1 M) for 4h, concentrated and extracted with DCM. The mixture was filtered and thesolvent removed in vacuo to give the title compound (4.4 g) as an orangeoil.

NMR (¹H, CDCl₃): δ 6.88-6.79 (m, 3H), 4.18 (t, 2H), 3.84 (s, 3H), 3.69(s, 3H), 3.55 (s, 2H), 2.87 (t, 2H), 2.56 (bs, 4H), 1.66 (bs, 4H), 1.46(bs, 2H).Preparation 32: 2-[4-Methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pent-4-enoic Acid Methyl Ester

Procedure:

To a solution of [4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-aceticacid methyl ester (2.1 g) in THF (dry, 15 ml) at −78° C. was slowlyadded lithium bis(trimethylsilyl)amide (1 M in THF, 8.2 ml). Thesolution was stirred at this temperature for 15 min before allyl bromide(0.59 ml) was added. After additional 30 min water and EtOAc were addedwith stirring. The mixture was allowed to warm to 25° C., layersseparated and the organic layer washed (brine), concentrated andsubmitted to column chromatography (silica gel, CH₂Cl₂/MeOH/NH₃) to givethe title compound (1.3 g) as a colourless oil.

NMR (¹H, CDCl₃): δ 6.90-6.80 (m, 3H), 5.76-5.67 (m, 1H), 5.10-4.98 (m,2H), 4.18 (bs, 2H), 3.83 (s, 3H), 3.65 (s, 3H), 3.56 (t, 1H), 2.86 (bs,2H), 2.83-2.73 (m, 1H), 2.65-2.45 (m, 5H), 1.65 (bs, 4H), 1.47 (bs, 2H).MS (m/z): 348 [MH]⁺.Preparation 33:2-[4-Methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pent-4-enoic AcidHydrochloride Salt

2-[4Methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pent-4-enoic acid methylester (1.3 g) in MeOH (2 ml), THF (2 ml) and water (2 ml) containing KOH(0.42 g) was heated at 45° C. for 1 h and then allowed to cool to 25° C.The mixture was evaporated to dryness. THF (5 ml) and conc. aqueous HCl(0.62 ml) were added, the mixture concentrated, extracted with DCM,filtered and the solvent removed in vacuo to give the title compound(1.2 g) as an off-white foam.

NMR (¹H, CD₃OD): δ 7.05 (d, 1H), 6.96 (dd, 1H), 6.91 (d, 1H), 5.81-5.70(m, 1H), 5.02 (dd, 1H), 4.92 (dd, 1H), 4.31 (dd, 2H), 3.83 (s, 3H),3.48-3.42 (m, 3H), 3.37-3.28 (m, 4H), 2.78-2.69 (m, 1H), 2.44-2.35 (m,1H), 1.91-1.84 (m, 4H), 1.72-1.63 (m, 2H). MS (m/z): 334 [MH]⁺.Preparation 34:2-[4-Methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pent-enoic Acid(3,4-dichlorophenyl)-amide

To a solution of2-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pent-4-enoic acidhydrochloride salt (0.46 g) in dry CH₂Cl₂ (4 ml), under N₂, was added,at 0° C., oxalyl chloride (0.11 ml) and DMF (cat). After 30 min thereaction mixture was concentrated to dryness in vacuo. To this materialwas added toluene (dry, 4 ml) and 3,4-dichloroaniline (0.20 g). Themixture was heated at 105° C. for 4 h, then partitioned between aqueousNaHCO₃ and EtOAc. The organic layer was washed (brine), concentrated andpurified by column chromatography (silica gel, CH₂Cl₂/MeOH/NH₃) to givethe title compound (0.35 g) as a slightly brown oil.

NMR (¹H, CDCl₃): δ 7.74 (s, 1H), 7.55 (bs, 1H), 7.31 (bs, 2H), 6.96 (bs,1H), 6.91-6.83 (m, 2H), 5.77-5.68 (m, 1H), 5.09 (d, 1H), 5.01 (d, 1H),4.23-4.16 (m, 2H), 3.85 (s, 3H), 3.53 (t, 1H), 2.99-2.91 (m, 1H), 2.83(t, 2H), 2.55 (bs, 4H), 1.68-1.62 (m, 4H), 1.47 (bs, 3H). MS (m/z): 477[MH]⁺, 2Cl.Preparation 35:2-[4-Methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-propanoic Acid MethylEster

To a solution of [4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-aceticacid methyl ester (0.60 g) in THF (dry, 6 ml) at −78° C. was slowlyadded lithium bis(trimethylsilyl)amide (1 M in THF, 2.3 ml). Thesolution was stirred at this temperature for 15 min before iodomethane(0.12 ml) was added, then allowed to warm to 25° C. After 16 aqueousNaHCO₃ and EtOAc were added with stirring, layers separated and theorganic layer washed (brine), concentrated and submitted to columnchromatography (silica gel, CH₂Cl₂/MeOH/NH₃) to give the title compound(0.27 g) as a slightly yellow oil.

NMR (¹H, CD₃OD): δ 6.88-6.75 (m, 3H), 4.12 (t, 2H), 3.80 (s, 3H),3.67-3.34 (m, 4H), 2.78 (t, 2H), 2.50 (bs, 4H), 1.65-1.37 (m, 9H). MS(m/z): 322 [MH]⁺.Preparation 36: 2-(3-Chloro-phenyl)-pent-4-enoic Acid{3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-4-methoxy-phenyl}-amide

The title compound was prepared, in an analogous manner to the compoundof Preparation 14, in 317 mg yield of brow oil (y=73%) from2-(3,4-dichloro-phenyl)-pent-4-enoic acid (200 mg).

MS (m/z): 457 [MH]⁺, 1Cl.Preparation 37:3-(3Chloro-phenyl)-5-hydroxy-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-pyrrolidin-2-one

The title compound was prepared, in an analogous manner to the compoundof Example 15, in 176 mg yield as brow oil (y=55%) from2-(3chloro-phenyl)-pent-4-enoic acid{4-methoxy-3-[2-(4-methylpiperidin)-1-yl-ethoxy]-phenyl}-amide (317 mg).

MS (m/z): 459 [MH]⁺, 1Cl.Preparation 38:5-(tert-Butyl-dimethyl-silanyloxy)-2-(3,4-dichloro-phenyl)-pentanoicAcid

Procedure:

A solution of (3,4-Dichloro-phenyl)-acetic acid (1.5 g, 7.3 mmol) inanh. THF (15 ml), under N₂, was treated with lithium bis(trimethylsilyl)amide (1M solution in THF, 2.2 eq., 16 ml) at −78° C. for 30 minutesbefore (3-bromo-propoxy)-tert-butyl-dimethyl-silane (1.7 eq., 2.9 ml)was added. The mixture was stirred for 2 hours at room temperature andquenched with saturated solution of Ammonium Chloride (20 ml). Theproduct was extracted with ethyl acetate (2×15 ml) and the organic phasewas washed with brine (1×15 ml), dried over Na₂SO₄ and concentrated invacuo. The crude product was purified by flash chromatography (silicagel, AcOEt/cHex 1/1 then AcOEt) to give 16 g of the title product as apale yellow oil (56%).

NMR (¹H, DMSO-d6): δ 12.6 (sb, 1H), 7.58 (d, 1H), 7.53 (d, 1H), 7.27(dd, 1H), 3.59 (t, 1H), 3.54 (t, 2H), 2.00 (m, 1H), 1.7 (m, 1H), 1.4 (m,1H), 1.3 (m, 1H), 0.82 (s, 9H), −0.01 (s, 3H), −0.02 (s, 3H).Preparation 39:5-(tert-Butyl-dimethyl-silanyloxy)-2-(3,4-dichloro-phenyl)-pentanoicAcid [4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide

Procedure:

To a solution of5-(tert-butyl-dimethyl-silanyloxy)-2-(3,4-dichloro-phenyl)-pentanoicacid (780 mg, 2.1 mmol) in anh. DMF (5 ml), under N₂, was added4methoxy-3-(2-piperidin-1-yl-ethoxy)-phenylamine (1 eq., 523 mg)followed by 1-hydroxybenzotriazole (1.2 eq., 360 mg) and1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 eq., 476mg). The reaction was stirred at room temperature for 16 h. AcOEt wasadded (10 ml) and the organic phase was washed with H₂O (10 ml), NaHCO₃sat. (10 ml) brine (10 ml), dried over Na₂SO₄ and concentrated in vacuoto obtain the title product as a pale yellow foam 1.25 g (98%).

NMR (¹H, CDCl₃): δ 7.75 (s, 1H), 7.45 (s, 1H), 7.3 (d, 1H), 7.2 (m, 1H),7.00 (d, 1H), 6.7 (d, 1H), 4.1 (m, 2H), 3.75 (s, 2H), 3.5 (m, 2H), 2.6(m, 4H), 1.6-1.3 (m, 8H), 0.9 (s, 9H), 0.5 (s, 6H)Preparation 40: 2-(3,4dichloro-phenyl)-5-hydroxy Pentanoic Acid[4-methoxy-3-(2-piperidin-1yl-ethoxy)-phenyl]-amide

Procedure:

To a solution of5-(tert-butyl-dimethyl-silanyloxy)-2-(3,4-dichloro-phenyl)-pentanoicacid [4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide (780 mg, 2.1mmol) in anh. DMF (2 ml), under N₂, triethylamine trihydrofluoride (0.5eq., 0.17 ml) was added. The reaction was stirred at room temperaturefor 18 h. AcOEt was added (10 ml) and the organic phase was washed withNaHCO₃ sat (10 ml), dried over Na₂SO₄ and concentrated in vacuo toobtain the title product as a white foam 1 g (100%).

NMR (¹H, DMSO-d6): δ 9.98 (s, 1H), 7.6 (m, 2H), 7.34 (d, 1H), 7.29 (d,1H), 7.07 (d, 1H), 7.2 (m, 1H), 6.85 (d, 1H), 4.42 (t, 1H), 3.98 (t,2H), 3.69 (s, 3H), 3.64 (t, 1H), 3.39 (q, 2H), 2.66 (bs, 2H), 2.46 (bm,4H), 2.0 (m, 1H), 1.7 (m, 1H), 1.49 (bm, 4H), 1.37 (m, 2H), 1.33 (m,2H). MS (m/z): 495 [MH]⁺, 2Cl.Preparation 41: 2-Chloro-1-(4-metyl-piperidin-1-yl)-ethanone

Procedure:

To a solution of 4-metylpiperidine (10 g, 100 mmol) in anh. CH₂Cl₂ (100ml) was added, at 0° C. and under N₂, TEA (2.5 eq, 35 ml) andchloroacetyl chloride (1.2 eq, 9.6 ml). The reaction was stirred at roomtemperature for 6 hours. The solution was diluted with water (60 ml) andextracted with ethyl acetate (3×100 ml). The combined organic extractswere dried over anhydrous Na₂SO₄, filtered and concentrated to drynessin vacuo to give 13.6 g of the title product (yield: 78%).

NMR (¹H, CDCl₃): δ 4.57 (d, 1H), 4.11 (d, 2H), 3.82 (d, 1H), 3.12 (t,1H), 2.67 (t, 1H), 1.67 (m, 4H), 1.22 (m, 1H), 1.02 (d, 3H). MS (m/z):176 [MH]⁺, 1ClPreparation 42:2-(2-Methoxy-5-nitro-phenoxy)-1-(4-methyl-piperidin-1-yl)-ethanone

Procedure:

To a solution of 2-methoxy-5-nitrophenol (350 mg, 2.06 mmol) in DMF (11ml) at room temperature were added K₂CO₃ (312 mg, 2.2 mmol) and2-chloro-1-(4-methyl-piperidin-1-yl)-ethanone (396 mg, 2.2 mmol). Thesuspension was stirred at room temperature for 24 hours. The suspensionwas diluted with water (20 ml) and extracted with EtOAc (2×20 ml), thecombined organic phases were washed with NaOH 1N (3×20 ml), dried overNa₂SO₄, filtered and concentrated to dryness in vacuo, to obtain thetitle product as a red oil (0.38 g, 58%)

NMR (¹H, CDCl₃): δ 8.00 (dd, 1H), 7.76 (d, 1H), 6.98 (d, 1H), 4.87 (s,3H), 4.55 (d, 1H), 4.02 (s, 3H), 3.85 (d, 1H), 3.13 (t, 1H), 2.68 (t,1H), 1.68 (m, 2H), 1.27 (m, 2H), 1.01 (d, 3H). MS (m/z): 309 [MH]⁺.Preparation 43:1-[2-(2-Methoxy-5-nitro-phenoxy)-ethyl]-4-methyl-piperidine

Procedure:

2-(2-Methoxy-5-nitro-phenoxy)-1-(4-methyl-piperidin-1-yl)-ethanone (11g, 36 mmol) was dissolved in anh. THF (20 ml), 1M BH_(s)THF (2.2 eq,78.5 ml) was added dropwise to the solution, and the mixture was heatedat reflux for 4 hours. The solution was cooled to room temperature,CH₃OH (100 ml) was added, and the solvent was removed under reducedpressure. The residue was dissolved in CH₃OH (100 ml) , 6N HCl (200 ml)was added, and the solution was heated to reflux for 0.5 h. The CH₃OHwas removed under reduced pressure and the remaining aqueous solutionwas made basic (pH>10) with 2.5N NaOH. The basic solution was extractedwith ethyl acetate (3×80 ml). The combined organic extracts were driedover anhydrous Na₂SO₄ and the solvent was removed under reduced pressureto give 9.4 g of the title product as a red oil. (yield: 89%)

NMR (¹H, CDCl₃): δ 7.91 (dd, 1H), 7.80 (d, 1H), 6.90 (d, 1H), 4.21 (t,2H), 3.96 (s, 3H), 2.97 (m, 2H), 2.85 (t, 2H), 2.12 (m, 2H), 1.64 (m,2H), 1.4 (m, 1H), 1.29 (m, 2H), 0.92 (d, 3H). MS (m/z): 295 [MH]⁺.Preparation 44:4-Methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenylamine

Procedure:

To a solution of1-[2-(2-methoxy-5-nitro-phenoxy)-ethyl]-4-methyl-piperidine (9.5 g, 32.3mmol) in abs.EtOH (200 ml) were added Pd/C 10% (1 g) and the reactionmixture was hydrogenated at room temperature and at atmosphericpressure. After 5 hrs the reaction mixture was filtered through a celitepad and the solution was concentrated in vacuo to give 8.5 g of thetitle product as a brown solid (yield: 99%).

NMR (¹H, DMSO-d₆): δ 6.61 (d, 1H), 6.26 (d, 1H), 6.04 (dd, 1H), 4.60(bs, 2H), 3.91 (t, 2H), 3.58 (s, 3H), 2.85 (m, 2H), 2.61 (t, 2H), 1.97(m, 2H), 1.52 (m, 2H), 1.3 (m, 1H), 1.1 (m, 2H), 0.86 (d, 3H).

Preparation 45: 2-(3,4-Dichloro-phenyl)-pent-4-enoic acid(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-amide

The title compound was prepared in an analogous manner to the compoundof preparation 14

NMR (¹H, CDCl₃): δ 7.50 (bs, 1H), 7.43 (d, 1H), 7.25 (dd, 1H), 7.21 (bs,1H), 6.92 (dd, 1H), 6.78 (d, 1H), 5.74 (m, 1H), 5.13 (d, 1H), 5.03 (d,1H), 4.14 (t, 2H), 3.81 (s, 3H), 3.48 (t, 1H), 3.03 (d, 2H), 2.95 (m,1H), 2.86 (t, 2H), 2.55 (m, 1H), 2.18 (t, 2H), 1.65 (d, 2H), 1.4 (m,1H), 1.32 (t, 1H), 0.94 (d, 3H). MS (m/z): 491[MH]⁺, 2Cl.Preparation 46:3-(3,4Dichloro-phenyl)-5-hydroxy-1-(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-pyrrolidin-2-one

rocedure

To a solution 2-(3,4dichloro-phenyl)-pent-4-enoic add(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)ethoxy]-phenyl)-amide (0.25 g,0.51 mmol) in acetone/H₂O 8/1 (9.1/1.1 ml) was addedN-methyl-morpholine-N-oxide (2 eq, 120 mg) and OSO₄ 4 wt % sol. in water(cat., 100 μl). The reaction was stirred at room temperature for 18hours and then quenched with 10 ml of Na₂SO₃ sat. After 15 minutesstirring the diol was extracted with ethyl acetate (2×20 ml), dried overNa₂SO₄, filtered and concentrated to dryness in vacuo. The crude productwas then dissolved in THF/H₂O 1/1 (515 ml) and potassium periodate (1.5eq, 0.16 g) was added. The reaction was stirred at room temperature for2 hours. The solution was diluted with water (10 ml) and extracted withethyl acetate (3×10 ml). The combined organic extracts were dried overanhydrous Na₂SO₄ filtered and concentrated to dryness in vacuo. Flashchromatography of the crude product (silica gel, CH₂Cl₂/CH₃OH 4/1) gave0.14 g of the title product as a red oil. (yield: 57% in 2 steps)

NMR (¹H, DMSO-d6): δ 7.61 (m, 2H), 7.32 (dd, 1H), 7.25 (bs, 1H), 7.07(dd, 1H), 6.95 (d, 1H), 6.45 (d, 1H), 5.61 (m, 1H), 4.20 (t, 1H), 4.01(t, 2H), 3.74 (s, 3H), 2.67 (t, 2H), 2.90 (d, 2H), 2.45 (m, 1H), 2.35(m, 1H), 2.20 (t, 2H), 1.56 (d, 2H), 1.23 (t, 2H), 1.3 (m, 1H), 0.87 (d,3H).

MS (m/z): 493 [MH]⁺, 2Cl.Preparation 47: (3,4-Dichloro-phenyl)-acetic acid but-2-enyl Ester

Procedure: To a solution of 3,4-dichloro-phenylacetic acid (2 g, 9.7mmol) in anh. CH₂Cl₂ (40 ml), under N₂, was added, at 0° C., oxalylchloride (1.9 eq., 1.6 ml) and DMF (cat). The reaction was stirred atroom temperature for 3 hours. The reaction mixture was concentrated todryness in vacuo and the crude intermediate was then dissolved, underN₂, in anh. CH₂Cl₂ (40 ml). Crotyl alcohol (2 eq, 1.7 ml) and pyridine(1.1 eq., 1.2 ml) were added to the reaction mixture at roomtemperature. The reaction was stirred at room temperature for 18 hoursand then quenched with ammonium chloride (40 ml). The product wasextracted with ethyl acetate (3×25 ml) dried over Na₂SO₄, filtered andconcentrated to dryness in vacuo. The crude product was purified byflash chromatography (silica gel, AcOEt/cHex 19/1) to give 1.8 g of thetitle product as a pale yellow oil (72%).

NMR (¹H, DMSO-d₆): 7.57 (d, 1H), 7.56 (bs, 1H), 7.28 (dd, 1H), 5.74 (m,1H), 5.57 (m, 1H), 4.49 (d, 2H), 3.73 (s, 2H), 1.67 (d, 3H).Preparation 48: 2(3,4-Dichloro-phenyl)-3-methyl-pent-4-enoic Acid

Procedure:

To a stirred solution of lithium diisopropylamide (LDA) (1.8 ml, 3.5mmol) in anh. THF (2 ml) was added via a syringe, a solution of theester (3,4-dichloro-phenyl)-acetic acid but-2-enyl ester (0.38 g, 1.43mmol) in THF (2 ml). After 30 min the solution was treated withtrimethylsilyl chloride (0.45 mmol, 2.5 ml) and after a further 30 minat −78° C., the mixture was warmed to ambient temperature during 30 minwhich was stirred to and heated at reflux for 2 hrs. It was then cooledto ambient temperature before the addition of water (5 ml) andacidification to pH 2 using HCl 1M. The product was extracted into ethylacetate (3×10 ml). The combined organic extracts were dried overanhydrous Na₂SO₄ and the solvent was removed under reduced pressure.Flash chromatography of the crude product (cHex/EA 411 to 100% EA) gave0.14 g of the title product as a brown oil. (yield: 38%) which is amixture of diastereoisomers A/B 50/50.

NMR (¹H, DMSO-d₆): 12.62 (bs, 1H), 7.55 (m, 2H), 7.3 (dd, 1H), 5.81 (m,1H_(A)), 5.45 (m, 1H_(B)), 5.01 (dd, 2H_(A)), 4.81 (dd, 2H_(B)), 3.43(d, 1H), 2.78 (m, 1H), 1.06 (d, 3H_(A)), 0.74 (d, 3H_(B)).Preparation 49: 2-(3,4-Dichloro-phenyl)-3-methyl-pent-4-enoic Acid(4-methoxy-3-[2-(4-piperidin-1-yl)-ethoxy]-phenyl)-amide

The title compound was prepared in an analogous manner to the compoundof Preparation 14 mixture of diastereoisomers: A/B 60/40

NMR (¹H, DMSO-d₆): δ 10.05 (s, 1H_(B)), 9.94 (s, 1H_(A)), 7.65-7.50 (m,2H), 7.38 (dd, 1H_(A)), 7.34 (dd, 1H_(B)), 7.27 (bs, 1H_(B)), 7.23 (bs,1H_(A)), 7.06 (dd, 1H_(B)), 7.04 (dd, 1H_(A)), 6.85 (m, 1H), 5.84 (m,1H_(A)), 5.50 (m, 1H_(B)), 5.10-5.00 (m, 2H_(A)), 4.88-4.82 (m, 2H_(B)),3.97 (bs, 2H), 3.69 (s, 3H_(B)), 3.68 (s, 3H_(A)), 3.43 (m, 1H), 2.90(m, 1H), 2.63 (bs, 2H), 2.41 (bs, 4H), 1.48 (bs, 4H), 2.41 (bs, 2H),1.07 (3H_(B)), 0.76 (3H_(A)). MS (m/z): 491 [MH]⁺, 2ClPreparation 50: 2-(4-Chloro-phenyl)-pent-4-enoic Acid(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-amide

The title compound was prepared in an analogous manner to the compoundof Preparation 14

NMR (¹H, DMSO-d₆): δ 9.94 (S, 1H), 7.38 (m, 4H), 7.26 (d, 1H), 7.05 (dd,1H), 6.84 (d, 1H), 5.68 (m, 1H), 5.0 (dd, 2H), 3.95 (t, 2H), 3.70 (t,1H), 3.68 (S, 3H), 2.63 (t, 2H), 2.55 (m, 2H), 2.85 (m, 2H), 1.97 (m,2H), 1.531.08 (m, 4H), 1.3 (m, 1H), 0.86 (d, 3H). MS (m/z): 457 [MH]⁺,1Cl.Preparation 51: 2-(4-Chloro-phenyl)-pent-4-enoic Acid(4methoxy-3-[2-(4-piperidin-1-yl)-ethoxy]-phenyl)-amide

The title compound was prepared in an analogous manner to the compoundof Preparation 14

NMR (¹H, DMSO-d₆): δ 9.95 (s, 1H), 7.38 (m, 4H), 7.26 (d, 1H), 7.05 (dd,1H), 6.84 (d, 1H), 5.7 (m, 1H), 5.0 (dd, 2H), 3.95 (t, 2H), 3.70 (t,1H), 3.68 (s, 3H), 2.61 (t, 2H), 2.5 (m, 2H), 2.40 (m, 4H), 1.53-1.3 (m,6H). MS (m/z): 443 [MH]⁺, 1Cl.Preparation 52:3-(4-Chloro-phenyl)-5-hydroxy-1-(4-methoxy-3-[2-(4methyl-piperidin-1-yl)-ethoxy]-phenyl)-pyrrolidin-2-one

The title compound was prepared in an analogous manner to the compoundof Preparation 18.

Two isomers A) and B) are present in 54/46 ratio.

NMR (¹H, DMSO-d6): δ 7.4-7.31 (d+d, 4H), 7.45-6.95 (m, 3H), 6.5-6.4 (d,1H), 5.65 (m, 1H), 4.00 (t, 2H), 2.67 (t, 2H), 4.12-3.8 (m, 1H), 3.74(s, 3H) 2.87-2.0 (m, 2H), 2.08-2.0 (m, 4H), 1.56-1.1 (m, 4H), 1.3 (m,1H), 0.87 (d, 3H). MS (m/z): 459 [MH]⁺, 1Cl.Preparation 53:3-(4-Chloro-phenyl)-5-hydroxy-1-(4-methoxy-3-[2-piperidin-1-yl)-ethoxy]-phenyl)-pyrrolidin-2-one

The title compound was prepared in an analogous manner to the compoundof Preparation 18.

Two isomers A) and B) are present in 85/15 ratio.

NMR (¹H, DMSO-d6): δ 7.4-7.31 (d+d, 4H), 7.45-6.95 (m, 3H), 6.5-6.4 (d,1H), 5.65 (m, 1H), 4.00 (t, 2H), 2.62 (t, 2H), 4.12-3.8 (m, 1H), 3.74(s, 3H), 2.8-1.9 (m, 2H), 2.41 (m, 4H), 1.47 (m, 4H), 1.35 (m, 2H). MS(m/z): 445 [MH]⁺, 1Cl.Preparation 54:3-(2-Methoxy-5-nitro-phenoxymethyl)-piperidine-1-carboxylic Acidtert-butyl Ester

The product was prepared in an analogous manner to Preparation 6.

NMR (¹H, DMSO-d6): δ 7.91 (dd, 1H), 7.74 (d, 1H), 7.18 (d, 1H), 3.97 (d,2H), 3.94 (bs, 2H), 3.90 (s, 3H), 2.90 (bs, 2H), 1.90 (m, 1H), 1.80 (bs,1H), 1.60 (bs, 1H), 1.35 (bs, 2H), 1.35 (s, 9H). MS (m/z): 267[MH-Boc]⁺.Preparation 55:3-(5-Amino-2-methoxy-phenoxymethyl)-piperidine-1-carboxylic Acidtert-butyl Ester

The product was prepared in an analogous manner to Preparation 44.

NMR (¹H, DMSO-d6): δ 6.64 (d, 1H), 6.25 (d, 1H), 6.07 (dd, 1H), 4.69(bs, 2H), 3.73 (m, 2H), 3.67 (t, 1H), 3.60 (s, 3H), 2.8 (t, 1H), 1.9 (m,1H), 1.80 (m, 1H), 1.6 (m, 1H), 1.4 (m, 3H), 1.38 (s, 9H), 1.25 (m, 1H).MS (m/z): 237 [MH-Boc]⁺.Preparation 56:3-{5-[2-(3,4-Dichloro-phenyl)-pent-4-enoylamino]-2-methoxy-phenoxymethyl}-piperidine-1-carboxylicAcid tert-butyl Ester

The product was prepared in an analogous manner to Preparation 14.

NMR (¹H, DMSO-d6): δ 9.96 (s, 1H), 7.55 (m, 2H), 7.32 (d, 1H), 7.22 (s,1H), 7.01 (d, 1H), 6.82 (d, 1H), 5.66 (m, 1H), 5.03 (m, 1H), 4.94 (m,1H), 3.9 (bs, 1H), 3.70 (m, 4H), 3.66 (s, 3H), 2.78 (m, 2H), 2.70 (m,1H), 2.40 (m, 1), 1.83 (m, 1H), 1.75 (m, 1H), 1.57 (m, 1H), 1.31 (s,9H), 1.25 (m, 2H), MS (m/z): 463 [MH-Boc]⁺, 2Cl.Preparation 57:3-{5-[3-(3,4-Dichloro-phenyl)-5-hydroxy-2-oxo-pyrrolidin-1-yl]-2-methoxy-phenoxymethyl}-piperidine-1-carboxylicAcid tert-butyl Ester

The product was prepared in an analogous manner to Example 15.

MS (m/z): 465 [M-Boc]⁺, 2Cl.Preparation 58: N-(2-Hydroxy-4-nitro-phenyl)-acetamide

Procedure:

J. Med. Chem. 1998, 41, 13, 2308.

NMR (¹H, DMSO-d6): δ 10.99 (bs, 1H), 9.51 (s, 1H), 8.28 (d, 1H), 7.71(dd, 1H), 7.66 (d, 1H), 2.2 (s, 3H).Preparation 59: N-[4-Nitro-2-(2-piperidin-1-yl-ethoxy)-phenyl)-acetamide

The product was prepared in an analogous manner to Preparation 6.

NMR (¹H, CDCl₃): δ 8.72 (bs, 1H), 8.55 (d, 1H), 7.91 (dd, 1H), 7.80 (d,1H), 4.25 (t, 2H), 2.77 (t, 2H), 2.50 (m, 4H), 2.26 (s, 3H), 1.62 (m,4H), 1.48 (m, 2H). MS (m/z): 308 [MH]⁺.Preparation 60: N-[4-Amino-2-(2-piperidin-1-yl-ethoxy)-phenyl)-acetamide

The product was prepared in an analogous manner to Preparation 10.

NMR (¹H, DMSO-d6): δ 8.63 (s, 1H), 7.23 (d, 1H), 6.25 (d, 1H), 6.07 (dd,1H), 4.90 (s, 2H), 3.96 (t, 2H), 2.61 (t, 2H), 2.20 (s, 3H), 2.41 (m,4H), 1.48 (m, 4H), 1.37 (m, 2H). MS (m/z): 278 [MH]⁺.Preparation 61: 2-(3,4-Dichloro-phenyl)-pent-4-enoic Acid[4-acetylamino-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide

Procedure:

To a solution of 2-(3,4dichloro-phenyl)pent-4-enoic acid (210 mg, 1.08mmol) in dry DMF (5 ml) were added HOBt (292 mg, 2 eq), EDC (310 mg, 1.5eq) and TEA (0.376 ml, 2.5 eq). After 5 min. was addedN-[4-Amino-2-(2-piperidin-1-yl-ethoxy)-phenyl)-acetamide (300 mg, 1 eq)dissolved in DMF (7 ml). After three days AcOEt was added, the organicphase was washed with 5% aq. NaHCO₃ and water, dried over Na₂SO₄ andconcentrated in vacuo to give 398 mg of crude product, that was purifiedby flash chromatography (CH₂Cl₂/MeOH 9/1) to give 265 mg of the titlecompound (49% yield).

NMR (¹H, DMSO-d6): δ 10.1 (s, 1H), 8.92 (s, 1H), 7.77 (d, 1H), 7.61 (m,2H), 7.40 (d, 1H), 7.38 (dd, 1H), 7.05 (dd, 1H), 5.73 (m, 1H), 5.03 (dd,2H), 4.06 (t, 2H), 3.8 (t, 1H), 2.8 (m, 1H), 2.67 (t, 2H), 2.44 (m, 4H),2.4 (m, 1H), 2.05 (s, 3H), 1.50 (m, 4H), 1.40 (m, 2H). MS (m/z): 504[MH]⁺, 2Cl.Preparation 62:N-[4-[3-(3,4-Dichloro-phenyl)-5-hydroxy-2-oxo-pyrrolidin-1-yl]-2-(2-piperidin-1-yl-ethoxy)-phenyl]-acetamide

The product was prepared in an analogous manner to Example 15.

The product is a 60/40 mixture of a/b diastereoisomers.

NMR (¹H, DMSO-d6): δ 9.01 (s, 1H), 7.84 (d, 1H), 7.69 (d, 1Ha), 7.63 (m,2H), 7.42 (dd, 1Hb), 7.40 (d, 1Ha), 7.32 (dd, 1Ha), 7.25 (d, 1Hb), 7.13(dd, 1Ha), 7.02 (dd, 1Hb), 6.59 (d, 1Hb), 6.51 (d, 1Ha), 5.74, (m, 1Ha),5.68 (m, 1Hb), 4.21 (m, 1Ha), 4.09 (t, 2H), 3.90 (m, 1Hb), 2.95 (m,1Hb), 2.68 (m, 2H), 2.5 (m, 1Ha), 2.44 (m, 4H), 2.35 (m, 1Ha), 2.07 (s,3H), 1.95 (m, 1Hb), 1.49 (m, 4H), 1.38 (m, 2H) . MS (m/z): 506 [MH]⁺,2Cl.Preparation 63: 2-(3,4-Dichloro-phenyl)-propionic Acid Methyl Ester

Procedure:

A solution of methyl-3,4-dichloro-phenylacetate (2 g, 9.13 mmol) in anh.THF (30 ml), under N₂, was treated with lithium bis(trimethylsilyl)amide (1 M solution in THF, 1.1 eq., 10 ml) at −78° C. for 30 minutesbefore methyl iodide (1.2 eq., 0.67 ml) was added. The mixture wasstirred for 18 hours at room temperature, then quenched with water (20ml) and extracted with ethyl acetate (2×15 ml). The organic phase waswashed with brine (1×15 ml), dried over Na₂SO₄ and concentrated in vacuoto give 1.68 g of the title product as a orange oil (79%), that was usedas a crude.

NMR (¹H, CDCl₃): δ 7.20 (m, 2H), 7.0 (dd, 1H), 3.50 (s, 3H), 3.50 (m,1H), 1.3 (d, 3H).Preparation 64: 2-(3,4-Dichloro-phenyl)-2-methyl-pent-4-enoic AcidMethyl Ester

Procedure:

A solution of 2-(3,4-dichloro-phenyl)-propionic acid methyl ester (1.66g, 7.12 mmol) in anh. THF (25 ml), under N₂, was treated with lithiumbis(trimethylsilyl) amide (1M solution in THF, 1.1 eq., 7.8 ml) at −78°C. for 30 minutes before allyliodide (1.2 eq., 0.78 ml) was added. Themixture was stirred for 2 hours at room temperature, then quenched withwater (20 ml) and extracted with ethyl acetate (2×15 ml). The organicphase was washed with brine (1×15 ml), dried over Na₂SO₄ andconcentrated in vacuo. The crude product was purified by flashchromatography (silica gel, cHex/AcOEt 9/1) to give 1.70 g of the titleproduct as a pale yellow oil (87%).

NMR (¹H, CDCl₃): δ 7.35 (m, 2H), 7.0 (dd, 1H), 5.40 (m, 1H), 4.95 (m,2H), 3.50 (s, 3H), 2.6 (m, 1H), 2.4 (m, 1H), 1.2 (s, 3H).Preparation 65: 2-(3,4-Dichloro-phenyl)-2-methyl-pent-4-enoic Acid

Procedure:

To a solution of 2-(3,4-dichloro-phenyl)-2-methyl-pent-4-enoic acidmethyl ester (0.908 g, 3.32 mmol) in MeOH (33 ml), was added NaOH 1M (3eq., 9.9 ml). The mixture was refluxed for 7 hours, then concentratedand washed with CH₂Cl₂. The aqueous phase was acidified to pH 3 withconc. HCl and extracted with CH₂Cl₂. The combined extracts were driedover Na₂SO₄ and concentrated in vacuo to give 806 mg of the titleproduct as a colorless oil (94%), that was used as crude.

NMR (¹H, CDCl₃): δ 7.30 (m, 2H), 7.10 (dd, 1H), 5.40 (m, 1H), 4.95 (m,2H), 2.60 (m, 1H), 2.45 (m, 1H), 1.50 (s, 3H).Preparation 66: 2-(3,4-Dichloro-phenyl)-2-methyl-pent-4-enoic Acid{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-amide

The product was prepared in an analogous manner to Preparation 14.

NMR (¹H, CDCl₃): δ 9.46 (bs, 1H), 7.30-6.80 (m, 5H), 6.59 (d, 1H), 5.35(m, 1H), 4.94-4.80 (m, 2H), 4.04 (t, 2H), 3.60 (s, 3H), 3.34 (m, 2H),3.10 (t, 2H), 2.70-2.28 (m, 4H), 1.64-1.29 (m, 1H), 1.43 (s, 3H), 1.25(m, 4H), 0.72 (d, 3H). MS (m/z): 505 [MH]⁺, 2Cl.Preparation 67:3-(3,4-Dichloro-phenyl)-5-hydroxy-1-(4-methoxy-3-[2-(4-methylpiperidin-1-yl)-ethoxy]-phenyl}-3-methyl-pyrrolidin-2-one

The product was prepared in an analogous manner to Example 15.

MS (m/z): 507 [MH]⁺, 2Cl.Preparation 68: 2-(3-Chloro-phenyl)-pent-4-enoic Acid

Procedure:

The reaction was carried out as described for Preparation 12 on 1.00 gof 3-chlorophenylacetic acid. The title compound (1.23 g) was recoveredas an orange oil.

NMR (¹H, DMSO-d6): δ 12.50 (bs, 1H), 7.15-7.40 (m, 4H), 5.60-5.80 (m,1H), 4.90-5.10 (m, 2H), 3.70 (t, 1H), 2.60-2.80 (m, 1H), 2.35-2.50 (m,1H).Preparation 69: 2-(3-Chloro-phenyl)-pent-4-enoic Acid[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide

The reaction was carried out on 500 mg of2-(3-chloro-phenyl)pent-4-enoic acid as described in Preparation 14. Thetitle compound (760 mg) was obtained as a brown oil.

NMR (¹H, CDCl₃): δ 7.35 (bs, 1H), 7.18-7.28 (m, 3H), 7.10 (bs, 1H), 6.83(dd, 1H), 6.75 (d, 1H), 5.64-5.80 (m, 1H), 4.95-5.12 (m, 2H), 4.10 (t,2H), 3.78 (s, 3H), 3.45 (t, 1H), 2.85-3.00 (m, 2H), 2.77 (t, 2H),2.40-2.60 (m, 5H), 1.52-1.65 (m, 4H), 1.36-1.47 (m, 2H). MS (m/z): 443[MH]⁺, 1Cl.Preparation 70:3-(3-Chloro-phenyl)-5-hydroxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one

Procedure:

The reaction was carried out on 2-(3-chloro-phenyl)-pent-4-enoic acid[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide (700 mg) asdescribed for Example 15 to give the title compound (430 mg, mixture oftwo diastereomers as a brown foam.

MS (m/z): 445[MH]⁺, 1Cl.Preparation 71: 2-(3-Trifluoromethyl-phenyl)-pent-4-enoic Acid

Procedure:

The reaction was carried out as described for Preparation 12 on 1.00 gof 3-trifluoromethylphenylacetic acid. The title compound (1.18 g) wasrecovered as a yellow gum.

NMR (¹H, DMSO-d6): δ 12.45 (bs, 1H), 7.50-7.70 (m, 4H), 5.60-5.75 (m,1H), 4.90-5.00 (m, 2H), 3.80 (t, 1H), 2.65-2.80 (m, 1H), 2.40-2.50 (m,1H).Preparation 72: 2-(3-Trifluoromethyl-phenyl)-pent-4-enoic Acid[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide

Procedure:

The reaction was carried out on 300 mg of2-(3-trifluoromethyl-phenyl)pent-4-enoic acid as described inPreparation 14. The title compound (450 mg) was obtained as a whitefoam.

NMR (¹H, DMSO-d6): δ 10.03 (s, 1H), 7.71 (bs, 1 H), 7.70 (d, 1H), 7.66(bs, 1H), 7.61 (d, 1H), 7.59 (t, 1H), 7.06 (dd, 1H), 6.86 (d, 1H), 5.72(m, 1H), 5.09 (d, 1H), 4.99 (d, 1H), 3.96 (bs, 2H), 3.80 (t, 1H), 3.67(s, 3H), 3.63 (bs, 2H), 2.8 (m, 1H), 2.6 (m, 1H), 2.41 (bs, 4H), 1.47(bm, 4H), 1.40 (bs, 2H). MS (m/z): 477 [MH]⁺.Preparation 73:3-(3-Trifluoromethyl-phenyl)-5-hydroxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one

Procedure:

The reaction was carried out on2-(3-trifluoromethyl-phenyl)-pent-4-enoic acid[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide (450 mg) asdescribed for Example 13 to give the title compound (285 mg, mixture oftwo diastereomers in 2.5/4 ratio) as a colourless oil.

NMR (¹H, CDCl₃) of the major product: δ 7.57-7.79 (m, 4H), 7.13 (dd,1H), 7.01 (d, 1H), 6.99 (d, 1H), 6.46 (d, 1 H), 5.65 (m, 1H), 4.30 (t,2H), 3.98 (t, 1H), 3.76 (s, 3H), 2.91 (m, 2H), 2.62 (bs, 4H), 2.50 (m,2H), 2.39 (m, 2H), 1.58 (bm, 4H), 1.41 (bs, 2H).

MS (m/z): 479 [MH]⁺.Preparation 74: 2-(4-Fluoro-phenyl)-pent-4-enoic Acid

Procedure:

The reaction was carried out as described for Preparation 12 on 1.00 gof 4-fluoromethylphenylacetic acid. The title compound (1.26 g) wasrecovered as a white foam.

NMR (¹H, DMSO-d6): δ 12.40 (bs, 1H), 7.25-7.40 (m, 2H), 7.05-7.15 (m,2H), 5.60-5.75 (m, 1H), 4.90-5.05 (m, 2H), 3.60 (t, 1H), 2.60-2.15 (m,1H), 2.30-2.45 (m, 1H).Preparation 75: 2-(4-Fluoro-phenyl)-pent-4-enoic Acid[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide

Procedure:

The reaction was carried out on 600 mg of2-(4-fluoro-phenyl)-pent-4-enoic acid as described in Preparation 14.The title compound (880 mg) was obtained as an orange gum.

NMR (¹H, DMSO-d6): δ 9.94 (s, 1H), 7.41 (t, 2H), 7.28 (d, 1H), 7.14 (t,2H), 7.05 (dd, 1H), 6.85 (d, 1H), 5.69 (m, 1H), 5.08 (d, 1H), 4.98 (d,1H), 3.97 (t, 2H), 3.80 (t, 1H), 3.70 (t, 1H), 3.68 (s, 3H), 2.70 (m,1H), 2.63 (t, 2H), 2.40 (bm, 4H), 1.48 (bm, 4H), 1.37 (bs, 2H). MS(m/z): 427 [MH]⁺.Preparation 76:3-(4-Fluoro-phenyl)-5-hydroxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one

Procedure:

The reaction was carried out on 2-(4-fluoromethyl-phenyl)-pent-4-enoicacid [4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide (750 mg) asdescribed for Example 13 to give the title compound (570 mg, mixture oftwo diastereomers) as a brown foam.

MS (m/z): 429 [MH]⁺.

EXAMPLE 13-(3,4-Dichloro-phenyl)-3-hydroxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one

To a solution of methansulfonic acid2-(5-[3-(3,4-dichloro-phenyl)-2-oxo-pyrrolidin-1-yl]-2-methoxy-phenoxy)-ethylether (103 mg, 0.216 mmol) in DMF (5 ml) was added piperidine (1 eq, 22μl), Nal (cat.) and K₂CO₃ (1 eq, 15.5 μl). The reaction mixture washeated at 60° C. for 5 hours under atm N₂ and then 18 hours at roomtemperature in the presence of air. The reaction mixture was dilutedwith water (20 ml) and extracted with AcOEt (3×25 ml). The combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated invacuo The crude product was purified by flash chromatography (silicagel, CH₂Cl₂/CH₃OH 18/2) to give 1.6 mg of title product as a yellow oil(3.8%).

NMR (¹H, DMSO-d6): δ 7.68 (d, 1H), 7.62 (d, 1H), 7.48 (d, 1H), 7.40 (dd,1H), 7.12 (dd, 1H), 6.97 (d, 1H), 6.48 (s, 1H), 4.02 (t, 2H), 3.91-3.80(m, 2H), 3.74 (s, 3H). 2.64 (m, 2H), 2.51-2.3 (m, 2H), 2.42 (m, 4H),1.47-1.35 (m, 2H). MS (m/z): 479 [MH]⁺+2Cl

EXAMPLE 23-(3,4-Dichloro-phenyl)-3-hydroxy-1-[4-methoxy-3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrrolidin-2-one

The product was prepared in an analogous manner as for Example 1.

NMR (¹H, DMSO-d6): δ 7.67 (d, 1H), 7.62 (d, 1H), 7.48 (d, 1H), 7.40 (dd,1H), 7.12 (dd, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 4.05 (t, 2H), 3.90-3.80(m, 2H), 3.74 (s, 3H), 3.74 (s, 3H), 3.56 (m, 4H), 2.68 (m, 2H),2.49-2.34 (m, 2H), 2.48 (m, 4H). MS (m/z): 481 [MH]⁺+2Cl

EXAMPLE 33-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one

To a solution of crude methansulfonic acid2-(5-[3-(3,4-dichloro-phenyl)-2-oxo-pyrrolidin-1-yl]-2-methoxy-phenoxy)-ethylether (0.09 mmol) in DMF (2 ml) was added piperidine (1 eq, 9 μl), Nal(cat.) and DIPEA (1 eq, 15.5 μl). The reaction mixture was heated at100° C. for 3 hours. The reaction mixture was diluted with water (20 ml)and extracted with AcOEt (3×25 ml). The combined organic extracts weredried over Na₂SO₄, filtered and concentrated in vacuo The crude productwas purified by flash chromatography (silica gel, CH₂Cl₂/CH3OH 18/2) togive 1.6 mg of the title product as a pale yellow solid (3.8%).

NMR (¹H, CDCl₃): δ 0.7.56 (d, 1H), 7.45-7.43 (m, 2H), 7.18 (dd, 1H),6.96 (dd, 1H), 6.86 (d, 1H), 4.19 (t, 2H), 3.95-3.8 (m, 4H+2H),2.65-2.57 (m, 1H+4H), 2.25 (m, 1H), 1.9-1.5 (m, 6H). MS (m/z): 463.4[MH]⁺+2Cl

EXAMPLE 41-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-pyrrolidin-2-one

The title compound was prepared in an analogous manner to the compoundof Example 3.

NMR (¹H, CDCl₃): δ 7.72 (d, 1H), 7.45 (d, 1H), 7.42 (d, 1H), 7.33 (d,1H), 7,18 (dd, 1H), 6.90 (dd, 1H), 4.19 (t, 2H), 3.91 (dd, 2H), 3.84 (t,1H), 2.86 (t, 2H), 2.65 (m, 1H), 2.57 (m, 4H), 2.3 (m, 1H) 1.6-1.4 (m,6H). MS (m/z): 467 [MH]⁺, 3Cl.

EXAMPLE 51-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-3-hydroxy-pyrrolidin-2-one

1-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-pyrrolidin-2-one(26 mg, 0.055 mmol) was dissolved in DMF (1 ml), tBuOK (9 mg, 1.3 eq)was added and the mixture was stirred at room temperature in thepresence of air for 30 min. A saturated solution of NH₄Cl was added andextracted with CH₂Cl₂. The extracts were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromathography(silica gel, CH₂Cl₂/MeOH 9/1), to give 13 mg of the title product (49%yield).

NMR (¹H, CDCl₃): δ 7.70 (d, 1H), 7.63 (m, 2H), 7.43 (d, 1H), 7.42 (dd,1H), 7.28 (dd, 1H), 6.57 (s, 1H), 4.14 (t, 2H), 3.98 (m, 1H), 3.85 (m,1H), 2.69 (m, 2H), 2.53 (m, 1H), 2.45 (m, 4H), 2.35 (m, 1H), 1.47-1.35(m, 6H). MS (m/z): 483 [MH]⁺, 3Cl.

EXAMPLE 63-(3,4-Dichloro-phenyl)-1-(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-pyrrolidin-2-one

The title compound was prepared in an analogous manner to the compoundof Example 3.

NMR (¹H, CDCl₃): δ 0.7.57 (d, 1H), 7.44 (d+d, 1H+1H), 7.19 (dd, 1H),6.96 (dd, 1H), 6.86 (d, 1H), 4.17 (bt, 2H), 3.90 (m, 2H), 3.83 (t, 1H),3.86 (s, 3H), 3.00 (m, 2H). 2.84 (bt, 2H), 2.66 (m, 1H), 2.28 (m, 1H),2.10 (m, 2H), 1.6-1.2 (m, 5H), 0.93 (d, 3H). MS (m/z): 477 [MH]⁺+2Cl

EXAMPLE 7 3-(3,4-Dichloro-phenyl)-1(4methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one

3-(3,4-Dichloro-phenyl)-3-hydroxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one(17.2 mg, 0.035 mmol) was dissolved in concentrated hydrochloric acid(1.7 ml). The reaction was heated at 40° C. for 3 hours, and thenconcentrated to dryness in vacuo. A solution of saturated NaHCO₃ wasadded until pH>7 and the product was extracted with ethylacetate (2×10ml). The combined extracts were dried over anhydrous Na₂SO₄, filteredand concentrated to dryness in vacuo. The crude product was purified byflash chromatography (silica gel, AcOEt/CH₃OH 4/6) to give 11.8 mg oftitle product as a brown oil (55.2%).

NMR (¹H, CDCl₃): 8.05 (d, 1H), 7.78 (d, 1H), 7.63 (d, 1H), 7.48 (d, 1H),7.31 (t, 1H), 7.04 (dd, 1H), 6.88 (d, 1H), 4.45 (d, 2H), 4.20 (t, 2H),3.87 (s, 3H). 2.85 (t, 2H), 2.54 (m, 4H), 1.62 (m, 4H), 1.45 (m, 2H). MS(m/z): 461.1 [MH]⁺+2Cl

EXAMPLE 83-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-morpholin-4-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one

The product was prepared in an analogous manner to Example 7.

NMR (¹H, CDCl₃): δ 0.8.04 (d, 1H), 7.77 (dd, 1H), 7.72 (d, 1H), 7.48 (d,1H), 7.31 (t, 1H), 6.96 (dd, 1H), 6.88 (d, 1H), 4.45 (d, 2H), 4.21 (t,2H), 3.86 (s, 3H), 3.74 (m, 4H), 2.87 (t, 2H), 2.60 (m, 4H). MS (m/z):463 [MH]⁺+2Cl

EXAMPLE 91-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-1,5-dihydro-pyrrol-2-one

1-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-5hydroxy-pyrrolidin-2-one(51 mg, 0.1 mmol) was dissolved in TFA (1 ml). The reaction mixture wasstirred at room temperature for 6 hours, then concentrated in vacuo. Asaturated solution of NaHCO₃ was added and the mixture was extractedwith ethyl acetate, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash chromathography over silica gel(CH₂Cl₂/MeOH 95/5) to give 29 mg of the title product as a colorless oil(yield: 60%).

NMR (¹H, CDCl₃): δ 8.0 (d, 1H), 7.83 (d, 1H), 7.73 (dd, 1H), 7.46 (d,1H), 7,32 (d, 1H), 7.30 (m, 1H), 6.96 (dd, 1H), 4.43 (d, 2H), 4.21 (t,2H), 2.85 (t, 2H), 2.56 (m, 4H), 1.5-1.4 (m, 6H). MS (m/z): 465 [MH]⁺,3Cl.

EXAMPLE 103-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one

The title product was prepared in an analogous manner to Example 7.

NMR (¹H, CDCl₃): δ 0.8.06 (d, 1H), 7.78 (dd, 1H), 7.64 (d, 1H), 7.49 (d,1H), 7.32 (t, 1H), 7.05 (dd, 1H), 6.89 (d, 1H), 4.45 (d, 2H), 4.22 (t,2H), 3.87 (s, 3H), 2.99 (t, 2H), 2.68 (m, 4H), 1.83-1.77 (m, 4H). MS(m/z): 447 [MH]⁺+2Cl

EXAMPLE 113-(3-Fluoro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one

The title compound was prepared in an analogous manner to the compoundof Example 3.

NMR (¹H, CDCl₃): δ 7.55-7.70 (m, 3H), 7.25-7.40 (m, 2H), 6.95-7.10 (m,2H), 6.85 (d, 1H), 4.40 (d, 2H), 4.10-4.20 (m, 2H), 3.85 (s, 3H), 2.85(t, 2H), 2.45-2.60 (m, 4H), 1.55-1.70 (m, 4H), 1.35-1.50 (m, 2H). MS(m/z): 411[MH]⁺.

EXAMPLE 123-(3,4-Dichloro-phenyl)-1-(-3-[2-(4,4-difluoro-piperidin-1-yl)-ethoxy]-4-methoxy-phenyl)-1,5-dihydro-pyrrol-2-one

The title compound was prepared in an analogous manner to the compoundof Example 3.

NMR (¹H, CDCl₃): δ 8.06 (d, 1H), 7.78 (dd, 1H), 7.76 (d, 1H), 7.50 (d,1H), 7.33 (t, 1H), 6.99 (bd, 1H), 6.90 (d, 1H), 4.44 (d, 2H), 4.22 (m,2H), 3.87 (s, 3H), 2.95 (m, 2H), 2.75 (m, 4H), 2.05 (m, 4H). MS (m/z):497.3 [MH]⁺+2Cl

EXAMPLE 133-(3-Fluoro-phenyl)-5-hydroxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one

To a solution of 2-(3-fluoro-phenyl)-pent-4-enoic acid[4methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide (85 mg, 0.2 mmol) inTHF/H₂O (5/1, 4 mL) was added OsO₄ (4% wt in water, 0.02 mmol) and NalO₄(86 mg, 0.4 mmol). After 18 hours the suspension was diluted with waterand the aqueous phase was extracted with EtOAc (2×). The combinedorganic phases were dried over Na₂SO₄, filtered and concentrated todryness in vacuo. The crude was purified by flash chromatography(CH₂Cl₂/MeOH/NH₄OH 95/5/0.5) to give 65 mg of title product as a brownoil. (y=75%) MS (m/z): 29[MH]⁺.

EXAMPLE 141-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-5-hydroxy-pyrrolidin-2-one

The title compound was prepared in an analogous manner to the compoundof Example 13. Two isomers A) and B) are present in 1:2 ratio.

NMR (¹H, DMSO-d6):

A) δ 7.70-7.10 (m, 6H), 6.58 (d, 1H), 4.25 (t, 1H), 5.74 (m, 1H), 4.13(bs, 2H), 2.63 (bs, 2H), 2.3-2.5 (m, 2H), 1.36-1.50 (bs, 10H).

B) δ 7.70-7.10 (m, 6H), 6.64 (d, 1H), 5.81 (m, 1H), 4.13 (bs, 2H), 3.93(m, 1H), 2.63 (bs, 2H), 2.92 (m, 1H), 1.93 (m, 1H), 1.36-1.50 (bs, 10H).

MS (m/z): 454 [MH] +2Cl.

EXAMPLE 153-3,4-Dichloro-phenyl)-1-(-3-[2-(4,4-difluoro-piperidin-1-yl)-ethoxy]-4-methoxy-phenyl)-5-hydroxy-pyrrolidin-2-one

The title compound was prepared in an analogous manner to the compoundof Example 13.

NMR (¹H, DMSO-d6): δ 7.7-7.6 (d, 1H), 7.6 (d, 1H), 7.4-7.3 (dd, 1H),7.25-7.12 (d, 1H), 7.10-6.95 (dd, 1H), 6.9 (d, 1H), 6.55-6.43 (d, 1H),5.66-5.60 (m, 1H), 4.03 (t, 2H), 4.2-3.85 (m, 1H), 3.74 (s, 3H), 2.77(t, 2H), 2.9-2.43 (m, 2H), 2.62 (m, 4H), 1.94 (m, 4H). MS (m/z): 515[MH]⁺+2Cl

EXAMPLE 163-(3-Fluoro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one

The title compound was prepared in an analogous manner to the compoundof Example 3.

NMR (¹H, CDCl₃): δ 7.56 (d, 1H), 7.30 (m, 1H), 7.08 (d, 1H), 7.02 (m, 1H), 6.95 (m, 1H), 6.93 (dd, 1H), 6.83 (d, 1H), 4.16 (t, 2H), 3.9-3.8 (m,3H), 3.82 (s, 3H), 2.84 (t, 2H), 2.64 (bs, 4H), 2.62 (m, 1H), 2.24 (m,1H), 1.60 (m, 4H), 1.43 (m, 2H). MS (m/z): 413[MH]⁺.

EXAMPLE 173-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-oneHydrochloride Salt

To3-(3,4-dichloro-phenyl)-5-hydroxy-1-[4-methoxy-3-(2-pyrrolidin-1-yl-ethoxy)phenyl]-pyrrolidin-2-one(17 mg) in DCM (dry, 0.3 ml) and Et₃SiH (0.03 ml) at 0° C. was addeddropwise a solution of trifluoroacetic acid (0.028 ml) in DCM (dry, 0.3ml). The mixture was allowed to warm to 25° C. After 8 h volatiles wereremoved in vacuo and the residue submitted to column chromatography(silica gel, CH₂Cl₂/MeOH /NH₃) to give, after conversion to thehydrochloride salt by treatment with excess HCl (1 M in Et₂O) followedby evaporation in vacuo and trituraton of the residue with Et₂O, thetitle compound (8 mg) as a slightly yellow film.

NMR (¹H, CD₃OD): δ 7.60 (d, 1H), 7.54-7.5 (m, 2H), 7.30 (dd, 1H), 7.12(dd, 1H), 7.08 (d, 1H), 4.35 (t, 2H), 4.02-3.92 (m, 3H), 3.89 (s, 3H),3.82-3.76 (m, m, 2H), 3.65 (t, 2H), 3.28-3.20 (m, 2H), 2.71-2.63 (m,1H), 2.32-2.16 (m, 3H), 2.11-2.01 (m, 2H). MS (m/z): 449 [MH]⁺, 2Cl.

EXAMPLE 183-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-methyl-pyrrolidin-2-oneHydrochloride Salt

The title compound (racemic, colourless foam. MS (m/z): 477 [MH]⁺, 2Cl.)was prepared from 2-(3,4-dichloro-phenyl)-2-methyl-pent-4-enoic acid and4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenylamine in an analogous mannerto the one described for Preparation 28 and Example 15.

Separation of the enantiomers was achieved by preparative HPLC using achiral stationary phase followed by salt formation as described forExample 19 to give Enantiomer 1 (slightly yellow solid) and Enantiomer 2(slightly yellow solid) of the title compound.

Enantiomer 1: NMR (¹H, CD₃OD): δ 7.60 (d, 1H), 7.56 (d, 1H), 7.48 (d,1H), 7.36 (dd, 1H), 7.10-7.02 (m, 2H), 4.34 (t, 2H), 3.92-3.82 (m, 4H),3.80-3.74 (m, 1H), 3.68 (bd, 2H), 3.53 (t, 2H), 3.06 (bt, 2H), 2.57-2.50(m, 1H), 2.36-2.28 (m, 1H), 2.00-1.93 (m, 2H), 1.88-1.73 (m, 3H),1.60-1.45 (m, 4H).

Enantiomer 2: NMR (¹H, CD₃OD): Essentially identical to the data forEnantiomer 1.

EXAMPLE 193-(3-Chloro-phenyl)-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-1,5-dihydro-pyrrol-2-oneHydrochloride Salt

The title compound was prepared, in an analogous manner to the compoundof Example 15 (HCl salt formation), in 44 mg yield as yellow solid(y=62%) from2-(3-chloro-phenyl)-5-hydroxy-1-{4-methoxy-3-[2-(4-methylpiperidin)-1-yl-ethoxy]-phenyl}-pyrrolidin-2-one(90 mg)

NMR (¹H, DMSO): δ 9.85 (bs, 1H), 8.11 (s, 1H), 7.94 (d, 1H), 7.90 (t,1H), 7.68 (d, 1H), 7.45 (m, 2H), 7.28 (dd, 1H), 7.06 (d, 1H), 4.62 (d,2H), 4.37 (t, 2H), 3.78 (s, 3H), 3.60 (m, 2H), 3.40 (m, 2H), 3.00 (m,2H), 1.82 (m, 2H), 1.60 (m, 1H), 1.45 (m, 2H), 0.90 (d, 3H).

MS (m/z): 441 [MH]⁺, 1Cl. Mp=99-101° C.

EXAMPLE 203-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H-pyridin-2-one

Procedure:

To a solution of 2-(3,4-dichloro-phenyl)-5-hydroxy pentanoic acid[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-amide (330 mg, 0.66 mmol)in anh. CH₂Cl₂ (6 ml), under N₂, Dess-Martin periodane (1.3 eq., 365mg), was added. The reaction was stirred at room temperature for 2 h.CH₂Cl₂ was added (10 ml) and the organic phase was washed with NaHCO₃sat.(10 ml), the aqueous phase was extracted with CH₂Cl₂ (3×10 ml), theorganic phases were dried over Na₂SO₄ and concentrated in vacuo to givea white foam. To a solution of the white foam in anh. CH₂Cl₂ (6 ml) ),under N₂, at 0° C., triethylamine (2.2 eq., 0.202 ml) and mesyl chloride(1.4 eq., 0.071 ml) were added. The reaction was stirred at roomtemperature for 16 h. CH₂Cl₂ was added (10 ml) and the organic phase waswashed with NaHCO₃ sat. (10 ml), dried over Na₂SO₄ and concentrated invacuo to obtain 23 mg of the title product as white foam.

NMR (¹H, DMSO-d6): δ 7.6 (s, 1H), 7.58 (d, 1H), 7.33 (dd, 1H), 6.98 (d,1H), 6.90 (bs, 1H), 6.80 (dd, 1H), 6.43 (d, 1H), 5.35 (m, 1H), 4.01 (t,2H), 4.00 (m, 1H), 3.76 (s, 1H), 2.70 (m, 1H), 2.60 (m, 1H), 2.58 (t,2H), 2.48 (bs, 2H), 1.50 (bs, 4H), 1.39 (bs, 2H). MS (m/z): 475 [MH]⁺,2Cl.

EXAMPLE 213-(3,4-Dichloro-phenyl)-1-[4methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-piperidin-2-oneHydrochloride Salt

Procedure:

To a solution of3-(3,4-dichloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H-pyridin-2-one(50 mg, 0.105 mmol) in anh. CH₂Cl₂ (1 ml), under N₂, was added triethylsilane (3 eq., 0.05 ml). The reaction was stirred at room temperaturefor 1 h, then trifluoroacetic acid (6 eq., 0.05 ml) was added. Thereaction was stirred at room temperature for 16 h. The reaction wasconcentrated in vacuo. The crude product was purified by flashchromatography (silica gel, CH₂Cl₂/MeOH from 24/1 to 4/1) to obtain 10mg of desired compound as the free base.

NMR (¹H, CDCl₃): δ 7.36 (d, 1H), 7.34 (d, 1H), 7.10 (dd, 1H), 6.90 (bs,3H), 4.37 (s, 2H), 3.80 (s, 3H), 3.8-3.6 (m, 5H), 3.42 (s, 2H), 2.83 (t,2H), 2.30 (m, 1H), 2.1-1.8 (m, 7H), 1.35 (m, 2H). MS (m/z): 477 [MH]⁺,2Cl.

From this material the hydrochloride salt was obtained as described forExample 17.

MS (m/z): 477 [MH]⁺, 2Cl.

EXAMPLE 223-(3,4-Dichloro-phenyl)-1-(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-3,4-dihydro-pyrrol-2-oneHydrochloride Salt

The title compound was prepared in an analogous manner to the onedescribed for the compound of Example 9 and 17 (HCl salt formation).

NMR (¹H, DMSO-d₆): δ 0.9.8+9.5 (2bs, 1H), 8.30 (d, 1H), 7.97 (dd, 1H),7.94 (t, 1H), 7.68 (d, 1H), 7.65 (d, 1H), 7.23 (dd, 1H), 7.03 (d, 1H),4.60 (d, 2H), 4.32 (t, 2H), 3.75 (s, 3H), 3.56 (d, 2H), 3.45 (m, 2H),3.01 (q, 2H), 1.78 (d, 2H), 1.57 (bm, 1H), 1.38 (q, 2H), 0.89 (d, 3H).MS (m/z): 477 [MH]⁺, 2Cl

EXAMPLE 233-(3,4-Dichloro-phenyl)-1-(4methoxy-3-[2-(4-methyl-piperidin-1yl)-ethoxy]-phenyl)-4-methyl-1,5-dihydro-pyrrol-2-oneHydrochloride Salt

The title compound was prepared in an analogous manner to the onedescribed for the compound of Example 13 followed by Example 9 and 17(HCl salt formation).

NMR (¹H, CD₃OD): δ 7.74 (d, 1H), 7.63 (d, 1H), 7.71 (d, 1H), 7.44 (dd,1H), 7.18 (dd, 1H), 7.09 (d, 1H), 4.53 (s, 2H), 4.34 (t, 2H), 3.56 (t,2H), 3.5-3.1 (bs, 4H), 3.9 (s, 3H), 2.26 (s, 3H), 1.91 (bs, 4H), 1.7(bs, 2H). MS (m/z): 475 [MH]⁺, 2Cl.

EXAMPLE 243-(4-Chloro-phenyl)-1-(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-3,4-dihydro-pyrrol-2-oneHydrochloride Salt

The title compound was prepared in an analogous manner to the onedescribed for the compound of Example 9 and 17 (HCl salt formation).

NMR (¹H, DMSO-d₆): δ 0.9.9+9.76 (2bs, 1H), 8.02 (d, 2H), 7.82 (t, 1H),7.67 (d, 1H), 7.51 (d, 2H), 7.27 (dd, 1H), 7.06 (d, 1H), 4.61 (d, 2H),4.36 (t, 2H), 3.78 (s, 3H), 3.59 (d, 2H), 3.48 (m, 2H), 3.04 (q, 2H),1.81 (m, 1H), 1.60 (bm, 1H), 1.44 (m, 2H), 1.01-0.92 (d-d, 3H). MS(m/z): 441 [MH]⁺, 1Cl.

EXAMPLE 253-(4-Chloro-phenyl)-1-(4-methoxy-3-[2-piperidin-1-yl)-ethoxy]-phenyl)-3,4-dihydro-pyrrol-2-oneHydrochloride Salt

The title compound was prepared in an analogous manner to the onedescribed for the compound of Example 9 and 17 (HCl salt formation).

NMR (¹H, DMSO-d₆): δ 9.8 (bs, 1H), 8.00 (d, 2H), 7.8 (t, 1H), 7.67 (d,1H), 7.50 (d, 2H), 7.27 (dd, 1H), 7.05 (d, 1H), 4.60 (d, 2H), 4.35 (t,2H), 3.78 (s, 3H), 3.6/4.4 (m, 4H), 3.00 (m, 2H), 1.85-1.65 (m, 4H), 1.4(m, 2H). MS (m/z): 427 [MH]⁺, 1Cl

EXAMPLE 263-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(piperidin-3-ylmethoxy)-phenyl]-pyrrolidin-one

The product was prepared in an analogous manner to Preparation 19.

NMR (¹H, DMSO-d6): δ 7.62-7.60 (m, 2H), 7.47 (t, 1H), 7.33 (dd, 1H),7.20 (dd, 1H), 6.94 (d, 1H), 3.98 (t, 1H), 3.85 (m, 2H), 3.75 (m, 2H),3.74 (s, 3H), 3.04 (m, 1H), 2.3 (m, 1H), 2.86 (m, 1H), 2.45 (m, 1H),2.55 (m, 1H), 2.2 (m, 1H), 1.87 (m, 1H), 1.79 (m, 1H), 1.58 (m, 1H),1.37 (m, 1H), 1.16 (m, 2H). MS (m/z): 449 [MH]⁺, 2Cl.

EXAMPLE 273-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(1-methyl-piperidin-3-ylmethoxy)-phenyl]-pyrrolidin-one

Procedure:

To a solution of3-(3,4-dichloro-phenyl)-1-[4-methoxy-3-(piperidin-3-ylmethoxy)-phenyl]-pyrrolidin-one(0.064 g, 0.14 mmol) in acetonitrile/dichloromethane 2/1 (3 ml), wasadded formaldehyde 37% in water (2.5 eq., 0.03 ml) and sodium triacetoxyborohydride (1.5 eq., 45 mg). After 3h the mixture was concentrated,diluited with CH₂Cl₂ and washed with NaHCO₃ 5%. The organic phase wasdried over Na₂SO₄ and concentrated in vacuo to give a colorless oil,that was purified by flash chromatography (CH₂Cl₂/MeOH 9/1) to give 52mg of the title compound (80% yield).

NMR (¹H. DMSO-d6): δ 7.62 (d, 1H), 7.61 (d, 1H), 7.47 (t, 1H), 7.33 (dd,1H), 7.03 (dd, 1H), 6.96 (d, 1H), 3.99 (t, 1H), 3.86 (dd, 2H), 3.77 (m,2t), 3.74 (s, 3H), 2.85-2.75 (bs, 1H), 2.7-2.6 (bs, 1H), 2.55 (m, 1H),2.21 (m, 1H), 2.16 (bs, 3H). 2.0 (bs, 1H), 2.0-1.8 (bs, 2H), 1.69 (m,1H), 1.62 (m, 1H), 1.6 (m, 1H), 1.48 (m, 1H). MS (m/z): 463 [MH]⁺, 2Cl.

EXAMPLE 28N-{4-[3-(3,4-dichlorophenyl)-2-oxo-2,5-dihydro-1H-pyrrol-1-yl]-2-[2-(1-piperidinyl)ethoxy]phenyl}acetamideHydrochloride

The product was prepared in an analogous manner to Example 9.

NMR (¹H, DMSO-d6): δ 10.2 (bs, 1H), 9.53 (s, 1H), 8.34 (d, 1H), 8.0 (dd,1H), 8.6(t, 1H), 7.87 (d, 1H) 7.79 (d, 1H), 7.72 (d, 1H), 7.24 (dd, 1H),4.66 (d, 2H), 4.39 (t, 2H), 3.52 (t, 2H), 3.52 (m, 2H), 2.99 (m, 2H),2.15 (s, 3H), 1.81 (m, 4H), 1.72 (m, 1H), 1.42 (m, 1H).

MS (m/z): 488 [MH]⁺, 2Cl.

Example 29N-{4-[3-(3,4-dichlorophenyl)-2-oxo-pyrrolidin-1-yl]-2-[2-(1-piperidinyl)ethoxy]phenyl}acetamideHydrochloride

The product was prepared in an analogous manner to Preparation 19.

NMR (¹H, DMSO-d6): δ 10.28 (bs, 1H), 9.55 (s, 1H), 7.89 (d, 1H), 7.63(d, 1H), 7.63 (m, 2H), 7.34 (dd, 1H), 7.11 (dd, 1H), 4.34 (t, 2H), 4.03(t, 1H), 3.90 (t, 2H), 3.49 (t, 2H), 3.48 (m, 2H), 2.97 (m, 2H), 2.57(d, 1H), 2.20 (d, 1H), 2.15 (s, 3H), 1.87 (m, 4H), 1.72 (m, 1H), 1.42(m, 1H). MS (m/z): 490 [MH]⁺, 2Cl.

EXAMPLE 303-(3,4-Dichloro-phenyl)-1-{4-methoxy-3-[2-(4-methyl)-piperidin-1-yl-ethoxy]-phenyl}-3methyl-pyrrolidin-2-oneHydrochloride

The product was prepared in an analogous manner to Preparation 19

NMR (¹H, DMSO-d6): δ 9.75 (bs, 1H), 7.69 (d, 1H), 7.62 (d, 1H), 7.57 (d,1H), 7.44 (dd, 1H), 7.15 (dd, 1H), 7.04 (d, 1H), 4.34 (t, 2H), 3.95 (m,1H), 3.69 (m, 1H), 3.72 (s, 3H), 3.58 (m, 2H), 3.40 (m, 2H), 3.05 (m,2H), 2.62 (m, 1H), 2.27 (m, 1H), 1.49 (s, 3H), 1.81 (m, 2H), 1.40 (m,2H), 1.51 (m, 1H), 0.92 (d, 3H). MS (m/z): 491 [MH]⁺, 2Cl.

EXAMPLE 313-(3-Chloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-oneHydrochloride Salt

Procedure:

The title compound (52 mg) was obtained as a brown solid in an analogousmanner to the one described for Example 21 followed by HCl saltformation as for Example 17.

NMR (¹H, DMSO): δ 9.80 (bs, 1H), 7.57 (d, 1H), 7.42-7.32, 7.28 (m, 4H),7.16 (dd, 1H), 7.04 (d, 1H), 4.32 (t, 2H), 3.95 (t, 1H), 3.89 (m, 2H),3.79 (s, 3H), 3.55 (d, 2H), 3.46 (m, 2H), 3.02 (q, 2H), 2.55 (m, 1H),2.20 (m, 1H), 1.82 (d, 2H), 1.70 (m, 2H), 1.40 (bm, 2H).

MS (m/z, free base): 429 [MH]⁺, 1Cl.

EXAMPLE 323-(3-Trifluoromethyl-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one

Procedure:

The racemic title compound was obtained in an analogous manner to theone described for Example 21. Separation of the enantiomers was achievedby preparative HPLC using a chiral stationary phase to give Enantiomer 1(yellow oil, 3 mg) and Enantiomer 2 (colourless gum, 6 mg) of the titlecompound.

Enantiomer 1: NMR (¹H, CDCl₃): δ 7.56-7.44 (m, 4H), 7.55 (d, 1H), 6.94(dd, 1H), 6.84 (d, 1 H), 4.17 (t, 2H), 3.88 (m, 3H), 3.83 (s, 3H), 2.84(m, 2H), 2.66 (m, 1H), 2.54 (bs, 4H), 2.30 (m, 1H), 1.61 (m, 4H), 1.43(m, 2H).

MS (m/z): 463 [MH]⁺.

Enantiomer 2: NMR (¹H, CDCl₃); MS: Essentially identical to the data forEnantiomer 1.

EXAMPLE 333-(3-Trifluoromethyl-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one

Procedure:

The title compound (20 mg) was obtained as a yellow oil in an analogousmanner to the one described for Example 11.

NMR (¹H, DMSO): δ 8.15 (bs, 1H), 8.13 (d, 1H), 7.66 (d, 1H), 7.63 (d,1H), 7.56 (t, 1H), 7.38 (t, 1H), 7.08 (dd, 1H), 6.90 (d, 1H), 4.49 (d,2H), 4.23 (t, 2H), 3.88 (s, 3H), 2.87 (t, 2H), 2.55 (bs, 4H), 1.65 (bm,4H), 1.46 (bs, 2H). MS (m/z): 461 [MH]⁺.

EXAMPLE 343-(3-Chloro-phenyl)-5-methoxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one

Procedure:

3-(3-Chloro-phenyl)-5-hydroxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)phenyl]-pyrrolidin-2-one (0.10 g) was treated with MeOH (dry, 4.5 ml)containing pyridinium 4-toluenesulfonate (68 mg) at reflux for 5 h. Themixture was partitioned between aqueous NaHCO₃ and EtOAc. The organiclayer was collected, concentrated and submitted to column chromatography(silica gel, CH₂Cl₂/MeOH /NH₃) to give the title compound (3:2 mixtureof diastereoisomers, 92 mg) as a brown oil.

NMR (¹H, DMSO): δ 7.5-6.95 (m, 7H), 5.48 (m, 1H), 4.12 (m, 0.6H), 4.02(t, 2H), 3.90 (m, 0.4H), 3.75 (s, 3H), 3.27 (s, 1.8H), 3.24 (s, 1.2H),2.85 (m, 0.4H), 2.64 (m, 2H), 2.56 (m, 0.6H), 2.42 (m, 4H), 2.35 (m,0.6H), 2.05 (m, 0.4H), 1.48 (m, 4H), 1.36 (m, 2H). MS (m/z): 459 [MH]⁺,1Cl.

EXAMPLE 353-(3-Chloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-oneHydrochloride

Procedure:

The title compound (52 mg) was obtained as a brown gum in an analogousmanner to the one described for Example 9 followed by HCl salt formationas for Example 17.

NMR (¹H, DMSO): δ 9.80 (bs, 1H), 8.11 (t, 1H), 7.94 (dt, 2H), 7.70 (t,1H), 7.40-7.50 (m, 2H), 7.28 (dd, 1H), 7.07 (d, 1H), 4.63 (d, 2H), 4.35(t, 2H), 3.79 (s, 3H), 3.57 (d, 2H), 3.50 (m, 2H), 3.03 (q, 2H), 1.85(d, 2H), 1.71 (m, 2H), 1.20-1.40 (m, 1H).

MS (m/z; free base): 427 [MH]⁺, 1Cl.

EXAMPLE 363-(4-Fluoro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-oneHydrochloride

Procedure:

The title compound (28 mg) was obtained as a yellow solid in ananalogous manner to the one described for Example 9 followed by HCl saltformation as for Example 17.

NMR (¹H, DMSO): δ 7.96 (m, 2H), 7.55 (t, 1H), 7.23 (d, 1H), 7.21 (dd,1H), 7.16 (m, 2H), 7.10 (d, 1H), 4.57 (d, 2H), 4.41 (t, 2H), 3.91 (s,3H), 3.58 (t, 2H), 3.74/3.11 (d/t, 2/2H), 1.99/1.85 (d/t, 2/2H),1.85/1.60 (m/m, 1/1 H). MS (m/z; free base): 411 [MH]⁺. Mp=207-209° C.

EXAMPLE 373-(4-Fluoro-phenyl)-1-[4-methoxy-3(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-oneHydrochloride Salt

Procedure:

The title compound (52 mg) was obtained as a yellow gum in an analogousmanner to the one described for Example 21 followed by HCl saltformation as for Example 17.

NMR (¹H, DMSO-d6): δ 9.8 (s, 1H), 7.59 (d, 1H), 7.34 (m, 2H), 7.17 (m,2H), 7.16 (dd, 1H), 7.04 (d, 1H), 4.32 (t, 2H), 3.93 (t, 1H), 3.80 (s,3H), 3.77 (m, 2H), 3.56 (m, 2H), 3.47 (q, 2H), 3.03 (m, 2H), 2.55 (m,1H), 2.15 (m, 1H), 1.70-1.80 (m, 4H), 1.45 (m, 2H). MS (m/z; free base):413 [MH]⁺.

EXAMPLE 381-{4-Methoxy-3-[2-(4-methyl-piperidin-1-yl)ethoxy]-phenyl}-3-(4-methyl-phenyl)-1,5-dihydro-pyrrol-2-oneHydrochloride Salt

5-Hydroxy-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-3-(4-methyl-phenyl)-pyrrolidin-2-one(80 mg, prepared in analogy to Preparations 13, 14 and 46) was dissolvedin TFA (2 ml). The reaction mixture was stirred at room temperatureovernight, then concentrated in vacuo. A saturated solution of NaHCO₃was added and the mixture was extracted with ethyl acetate, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashchromathography over silica gel (CH₂Cl₂/MeOH from 1/0 to 98/2) to give35 mg of the free base of the title compound. The product dissolved inCH₂Cl₂ (1.5ml), at 0° C., was treated with HCl (1 M in Et₂O, 0.17ml)followed by evaporation in vacuo and trituration of the residue withEt₂O to give the title compound (30 mg) as a white solid (40%).

NMR (¹H, CDCl₃): δ 12.4 (bs, 1H), 7.79 (d, 2H), 7.63 (d, 1H), 7.24 (dd,1H), 7.23 (d, 2H), 7.27 (s, 1H), 6.91 (d, 1H), 4.60 (t, 2H), 4.45 (d,2H), 3.85 (s, 3H), 3.70 (m, 2H), 3.42 (t, 2H), 2.90 (m, 2H), 2.38 (s,3H), 2.10/1.80 (m, 4H), 1.6 (m, 1), 1.05 (d, 3H); MS (m/z): 421 [M+H]⁺.

Examples 39-42 were prepared in analogy to Example 38 EXAMPLE 391-{4-Methoxy-3-[2-(piperidin-1-yl)-ethoxy]-phenyl}-3-(4methyl-phenyl)-1,5-dihydro-pyrrol-2-oneHydrochloride Salt

NMR (¹H, DMSO-d₆): δ 10.00 (bs, 1H), 7.87 (d, 2H), 7.68 (s, 1H), 7.67(s, 1H), 7.28 (dd, 1H), 7.22 (d, 2H), 7.06 (d, 1H), 4.57 (s, 2H), 4.38(t, 2H), 3.78 (s, 3H), 3.57/3.04 (d/t, 2H/2H), 3.48 (q, 2H), 2.32 (s,3H), 1.80/1.70 (m, 2H/2H), 1.70/1.40 (m, 1H/1H); MS (m/z): 407 [M+H]⁺.

EXAMPLE 403-(4-Bromo-phenyl)-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-1,5-dihydro-pyrrol-2-oneHydrochloride Salt

NMR (¹H, DMSO-d₆): δ 10.06 (bs, 1H), 7.95 (d, 2H), 7.83 (t, 1H), 7.67(d, 1H), 7.63 (d, 2H), 7,28 (dd, 1H), 7.06 (d, 1H), 4.60 (d, 2H), 4.38(t, 2H), 3.78 (s, 3H), 3.58 (m, 2H), 3.46 (m, 2H), 3.03 (m, 2H), 1.80(m, 2H), 1.60 (m, 1H), 1.46 (m, 2H), 0.92 (d, 3H); MS (m/z): 485 [M+H]⁺,1Br.

EXAMPLE 411-{4-Methoxy-3-[2-(4-methyl-piperidin-1-yl)ethoxy]-phenyl}-3-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-oneHydrochloride Salt

NMR (¹H, DMSO-d₆): δ 10.00/9.83 (bs, 1H), 8.20 (d, 2H), 7.96 (t, 1H),7.81 (d, 2H), 7.68 (d, 1H), 7,29 (dd, 1H), 7.07 (d, 1H), 4.65 (d, 2H),4.37 (t, 2H), 3.78 (s, 3H), 3.59 (m, 2H), 3.49 (m, 2H), 3.04 (m, 2H),1.80/1.40 (m, 4H), 1.60 (m, 1H), 0.91 (d, 3H); MS (m/z): 475 [M+H]⁺.

EXAMPLE 423-(2-Chloro-phenyl)-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-1,5-dihydro-pyrrol-2-oneHydrochloride Salt

NMR (¹H, DMSO-d₆): δ 9.90 (bs, 1H), 7.61 (d, 1H), 7.56 (t, 1H),7.50/7.36 (m/m 2H/2H), 7.26 (dd, 1H), 7.04 (d, 1H), 4.64 (d, 2H), 3.75(s, 3H), 3.34 (t, 2H), 3.56/3.01 (m/m, 2H/2H), 3.44 (m, 2H), 1.78/1.42(m/m, 2H/2H), 1.55 (bm, 1H), 0.88 (d, 3H); MS (m/z): 441 [M+H]⁺, 1Cl.

EXAMPLE 433-(3,4-Dichloro-phenyl)-3-hydroxy-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-pyrrolidin-2-one

3-(3,4-Dichloro-phenyl)-1-{4-methoxy-3-[2-(4methyl-piperidin-1-yl)-ethoxy]-phenyl}-pyrrolidin-2-one(730 mg, 1.53 mmol) was dissolved in DMF (10 ml), tBuOK (340 mg, 2 eq)was added and the mixture was stirred at room temperature in thepresence of air for 15 min. A saturated solution of NaHCO₃ was added andthe mixture extracted with CH₂Cl₂. The extracts were dried over Na₂SO₄and concentrated in vacuo. The residue was purified by columnchromathography (silica gel, CH₂Cl₂/MeOH 9/1), to give 260 mg of thetitle product (34%).

NMR (¹H, CDCl₃): δ 7.55 (m, 2H), 7.40 (d, 1H), 7.25 (d, 1H), 7.00 (d,1H), 6.85 (d, 1H), 4.15 (m, 2H), 3.80 (s, 3H), 3.70 (m, 1H), 3.00 (m,2H), 3.85 (m, 2H), 2.50 (m, 1H), 2.40 (m, 1H), 2.10 (m, 1H), 1.90-1.50(m, 6H), 1.25 (m, 2H), 0.85 (d, 3H). MS (m/z): 493 [MH]⁺ (2Cl).

EXAMPLE 443-(3,4-Dichloro-phenyl)-3-fluoro-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-pyrrolidin-2-oneHydrochloride Salt

3-(3,4-Dichloro-phenyl)-3-hydroxy-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)ethoxy]-phenyl}-pyrrolidin-2-one(210 mg, 0.43 mmol) was dissolved in CH₂Cl₂ (3 ml), (diethylamino)sulfurtrifluoride (DAST, 56 μl, 1 eq) was added at 0° C. and the mixture wasstirred for 1 h. A saturated solution of NaHCO₃ was added and themixture extracted with CH₂Cl₂. The extracts were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by preparative HPLC togive, after conversion to the hydrochloride salt by treatment withexcess HCl (1 M in Et₂O) followed by evaporation in vacuo andtrituration of the residue with Et₂O, 72 mg of the title product (34%).

NMR (¹H, Acetone-d₆): δ 13.2 (bs, 1H), 7.81 (d, 1H), 7.69 (m, 2H), 7.61(dd, 1H), 7.37 (bdd, 1H), 7.09 (d, 1H), 4.66 (bm, 2H), 4.15 (m, 2H),3.89 (s, 3H), 3.64 (bm, 2H), 3.45 (bm, 2H), 3.09 (bm, 2H), 3.05-2.09 (m,2H), 2.00-1.6 (bm, 5H), 1.02 (d, 3H). MS (m/z): 495 [MH]⁺(2Cl).

EXAMPLE 453-(3,4-Dichloro-phenyl)-1-{4-methoxy-3-[(1-methyl-pyrrolidin-2-yl)-methoxy]-phenyl}-pyrrolidin-2one

The product was prepared in an analogous manner to Example 27.

NMR (¹H, CD₃OD): δ 7.57 (d, 1H), 7.54 (d, 1H), 7.53 (d, 1H), 7.29 (dd,1H), 7.12/7.09 (m, 2H), 4.45/4.2 (m, 2H), 3.97 (m, 3H), 3.90 (m, 1H),3.87 (s, 3H), 3.70/3.25 (m, 2H), 3.14 (s, 3H), 2.65/2.30 (m, 2H),2.4/2.1 (m, 2H), 2.25/2.1 (m, 2H). MS (m/z): 449 [MH]⁺ (2Cl).

EXAMPLE 463-(3,4-Dichloro-phenyl)-1-{4-methoxy-3-[(1-methyl-pyrrolidin-2-yl)-methoxy]-phenyl}-3,4-dihydro-pyrrol-2-oneHydrochloride Salt

3-(3,4-Dichloro-phenyl)-1-{4-methoxy-3-[(1-methyl-pyrrolidin-2-yl)-methoxy]-phenyl}-pyrrolidin-2-one(134 mg, 0.276 mmol) was dissolved in DMF (1 ml), tBuOK (124 mg, 4 eq)was added and the mixture was stirred at room temperature in thepresence of air for 10 min. A saturated solution of NaHCO₃ was added andthe mixture extracted with CH₂Cl₂. The extracts were dried over Na₂SO₄and concentrated in vacuo. The residue was suspended in HCl 37% andheated in a microwave oven to 130° C. for 10 minutes. The solvent wasremoved and the residue was purified by column chromathography (silicagel, CH₂Cl₂/MeOH 9/1), to give, after conversion to the hydrochloridesalt by treatment with excess HCl (1 M in Et₂O) followed by evaporationin vacuo and trituraton of the residue with Et₂O, 10 mg of the titleproduct (8%).

NMR (¹H, CDCl₃): δ 12.65 (bs, 1H), 8.1 (s, 1H), 7.75 (d, 1H), 7.70 (s,1H), 7.50 (d, 1H), 7.4 (d, 1H), 7.35 (s, 1H), 6.90 (d, 1H), 4.85 (t,1H), 4.55 (d, 1H), 4.35 (d, 1H), 3.95 (s, 1H), 3.85 (s, 3H), 3.65 (bs,1H), 3.10 (s, 3H), 2.90 (s, 2H), 2.30 (bm, 2H), 2.10 (bm, 2H). MS (m/z):447 [MH]⁺ (2Cl).

1. A compound of formula (I) or a pharmaceutically acceptable salt

thereof: wherein: R₁ is hydrogen, hydroxy, fluoro, chloro, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkyloxy, C₁₋₆alkoxy or haloC₁₋₆alkoxy; m is 0when

is a double bond and m is 1 when

is a single bond; R₂ is hydrogen, halogen, cyano, nitro, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkyloxy, haloC₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy, C₁₋₆alkylthio, amino, mono- or di-C₁₋₆alkylamino or anN-linked 4 to 7 membered heterocyclic group; X is —(CH₂—CH₂)—,—(CH═CH)—, —(CH₂)₃—, —C(CH₃)₂—, —(CH═CH—CH₂)—, —(CH₂—CH═CH)— or a group—(CHR₅)— wherein R₅ is hydrogen, halogen, hydroxy, cyano, nitro,C₁₋₆alkyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyloxy, haloC₁₋₆alkyl, C₁₋₆alkoxy,haloC₁₋₆alkoxy or C₁₋₆alkylthio; R₃ is halogen, cyano, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₃₋₇cycloalkyloxy, C₁₋₆alkoxy, C₁₋₆alkylthio, hydroxy,amino, mono- or di-C₁₋₆alkylamino, an N-linked 4 to 7 memberedheterocyclic group, nitro, haloC₁₋₆alkyl, haloC₁₋₆alkoxy, aryl,arylC₁₋₆alkyl, arylC₁₋₆alkyloxy, arylC₁₋₆alkylthio or COOR₆, CONR₇R₈ orCOR₉ wherein R₆, R₇, R₈ and R₉ are independently hydrogen or C₁₋₆alkyl;p is 0, 1 or 2 or 3; R₄ is hydrogen, halogen, hydroxy, cyano, nitro,C₁₋₆alkyl, C₁₋₆alkanoyl, C₃₋₇cycloalkyl, C₃₋₇cycloalkyloxy,haloC₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₁₋₆alkylthio, amino, mono-or di-C₁₋₆alkylamino or an N-linked 4 to 7 membered heterocyclic group;Y is oxygen, sulfur, —CH₂— or NR₁₀ wherein R₁₀ is hydrogen or C₁₋₆alkyl;D is a single bond, —CH₂—, —(CH₂)₂— or —CH═CH—; and Z is an optionallysubstituted C-linked 4 to 7 membered heterocyclic group containing atleast one nitrogen, an optionally substituted N-linked 4 to 7 memberedheterocyclic group, or Z is —NR₁₁R₁₂ where R₁₁ and R₁₂ are independentlyhydrogen or C₁₋₆alkyl.
 2. A compound as claimed in claim 1, wherein X is—CH₂—.
 3. A compound as claimed in claim 1, wherein when

is a single bond, R₁ is hydrogen, hydroxy or C₁₋₆alkoxy.
 4. A compoundas claimed in claim 1 having the following formula (Ia):

wherein R₃, p, R₄, Y, D, Z,

are as defined in claim 1 and X₁ is —CH₂— or —HC(OH)—.
 5. A compound asclaimed in claim 1, wherein p is 1 or 2 and R₃ is/are halogen,particularly chloro or fluoro, attached at the 3 or the 3,4-positions ofthe phenyl ring.
 6. A compound as claimed in claim 1, wherein R₄ isC₁₋₆alkoxy (particularly methoxy), OCF₃, halogen or cyano.
 7. A compoundas claimed in claim 1 wherein D is —CH₂—.
 8. A compound as claimed inclaim 1, wherein Y is oxygen.
 9. A compound as claimed in claim 1,wherein Z is an optionally substituted N-linked 4 to 7 memberedheterocyclic group.
 10. A compound as claimed in claim 9, wherein Z ispiperidyl.
 11. A compound as claimed in claim 1 which is:3-(3,4-Dichloro-phenyl)-3-hydroxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one;3-(3,4-Dichloro-phenyl)-3-hydroxy-1-[4-methoxy-3-(2-morpholin-4-yl-ethoxy)-phenyl]-pyrrolidin-2-one;3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one;1-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-pyrrolidin-2-one;1-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-3-hydroxy-pyrrolidin-2-one;3-(3,4-Dichloro-phenyl)-1-(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-pyrrolidin-2-one;3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one;3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-morpholin-4-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one;1-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-1,5-dihydro-pyrrol-2-one;3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one;3-(3-Fluoro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one;3-(3,4-Dichloro-phenyl)-1-(-3-[2-(4,4-difluoro-piperidin-1-yl)-ethoxy]-4-methoxy-phenyl)-1,5-dihydro-pyrrol-2-one;3-(3-Fluoro-phenyl)-5-hydroxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one;1-[4-Chloro-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-(3,4-dichloro-phenyl)-5-hydroxy-pyrrolidin-2-one;3-(3,4-Dichloro-phenyl)-1-(-3-[2-(4,4-difluoro-piperidin-1-yl)-ethoxy]-4-methoxy-phenyl)-5-hydroxy-pyrrolidin-2-one;3-(3-Fluoro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one;3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one;3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3-methyl-pyrrolidin-2-onehydrochloride salt;3-(3-Chloro-phenyl)-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-1,5-dihydro-pyrrol-2-onehydrochloride salt;3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H-pyridin-2-one;3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-piperidin-2-one;3-(3,4-Dichloro-phenyl)-1-(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-3,4-dihydro-pyrrol-2-one;3-(3,4-Dichloro-phenyl)-1-(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-4-methyl-1,5-dihydro-pyrrol-2-one;3-(4-Chloro-phenyl)-1-(4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl)-3,4-dihydro-pyrrol-2-one;3-(4-Chloro-phenyl)-1-(4-methoxy-3-[2-piperidin-1-yl)-ethoxy]-phenyl)-3,4-dihydro-pyrrol-2-one;3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(piperidin-3-ylmethoxy)-phenyl]-pyrrolidin-one;3-(3,4-Dichloro-phenyl)-1-[4-methoxy-3-(1-methyl-piperidin-3-ylmethoxy)-phenyl]-pyrrolidin-one;N-{4-[3-(3,4-dichlorophenyl)-2-oxo-2,5-dihydro-1H-pyrrol-1-yl]-2-[2-(1-piperidinyl)ethoxy]phenyl}acetamide;N-{4-[3-(3,4-dichlorophenyl)-2-oxo-pyrrolidin-1-yl]-2-[2-(1-piperidinyl)ethoxy]phenyl}acetamide;3-(3,4-Dichloro-phenyl)-1-{4-methoxy-3-[2-(4-methyl)-piperidin-1-yl-ethoxy]-phenyl}-3-methyl-pyrrolidin-2-one;3-(3-Chloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one;3-(3-Trifluoromethyl-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one;3-(3-Trifluoromethyl-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one;3-(3-Chloro-phenyl)-5-methoxy-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one;3-(3-Chloro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one;3-(4-Fluoro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-1,5-dihydro-pyrrol-2-one;3-(4-Fluoro-phenyl)-1-[4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl]-pyrrolidin-2-one;1-{4-Methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-3-(4-methyl-phenyl)-1,5-dihydro-pyrrol-2-one;1-{4-Methoxy-3-[2-(piperidin-1-yl)-ethoxy]-phenyl}-3-(4-methyl-phenyl)-1,5-dihydro-pyrrol-2-one;3-(4-Bromo-phenyl)-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-1,5-dihydro-pyrrol-2-one;1-{4-Methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-3-(4-trifluoromethyl-phenyl)-1,5-dihydro-pyrrol-2-one;3-(2-Chloro-phenyl)-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-1,5-dihydro-pyrrol-2-one;3-(3,4-Dichloro-phenyl)-3-hydroxy-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-pyrrolidin-2-one;3-(3,4-Dichloro-phenyl)-3-fluoro-1-{4-methoxy-3-[2-(4-methyl-piperidin-1-yl)-ethoxy]-phenyl}-pyrrolidin-2-one;3-(3,4-Dichloro-phenyl)-1-{4-methoxy-3-[(1-methyl-pyrrolidin-2-yl)-methoxy]-phenyl}-pyrrolidin-2-one;3-(3,4-Dichloro-phenyl)-1-{4-methoxy-3-[(1-methyl-pyrrolidin-2-yl)-methoxy]-phenyl}-3,4-dihydro-pyrrol-2-one;or a pharmaceutically acceptable salt thereof.
 12. A process for thepreparation of a compound as defined in claim 1, which processcomprises: (a) reacting a compound of formula (II):

wherein R₁, R₂, R₃, R₄, m, p, X,

Y and D are as defined for formula (I), and L is a leaving group, with acompound of formula (Ill):Z-H  (III) wherein Z is as defined for formula (I); or (b) cyclising acompound of formula (IV):

wherein R₁, R₂, m, R₃, p, R4, Y, D, Z and

are as defined for formula (I) and G is a group —X═CH₂, wherein X is asdefined for formula (I), dehydrogenated as required; optionally followedby: removing any protecting groups; and/or converting a compound offormula (I) into another compound of formula (I); and/or forming apharmaceutically acceptable salt.
 13. A pharmaceutical compositioncomprising a compound as defined in claim 1 and a pharmaceuticallyacceptable carrier or excipient.
 14. A process for preparing apharmaceutical composition as defined in claim 13, the processcomprising mixing a compound a compound as defined in claim 1 and apharmaceutically acceptable carrier or excipient.
 15. A compound asdefined in claim 1 for use as a therapeutic substance.
 16. A compound asdefined in claim 1 for use in the treatment of a CNS disorder.
 17. Acompound as defined in claim 1 for use in the treatment of depression oranxiety.
 18. A method of treatment of a CNS disorder in a mammalincluding a human, which comprises administering to the sufferer atherapeutically safe and effective amount of a compound as defined inclaim
 1. 19. A method of treatment of depression and or anxiety in amammal including a human, which comprises administering to the sufferera therapeutically safe and effective amount of a compound as defined inclaim
 1. 20. Use of a compound as defined in claim 1 in the manufactureof a medicament for use in the treatment of a CNS disorder.
 21. The useof a compound as defined in claim 1 in the manufacture of a medicamentfor use in the treatment of depression or anxiety.